Although the non-vitamin K antagonist oral anticoagulants (NOACs) do not require routine monitoring, there are special circumstances in which laboratory measurement may be warranted. The objectives ...of this review are to summarize evidence on the influence of the NOACs on coagulation tests and provide practical guidance to clinicians on measurement and interpretation of coagulation assays in NOAC-treated patients. Selection of an appropriate assay for NOAC measurement depends on the drug, clinical objective, and assay availability. Separate suggestions for assay selection are provided depending on whether specialized assays are available or whether choice is limited to conventional coagulation assays such as the prothrombin time (PT) and activated partial thromboplastin time (APTT). The dilute thrombin time (TT) and ecarin-based assays are able to quantify dabigatran across a broad range of concentrations, but are not widely available. A normal TT excludes clinically relevant levels. A normal APTT probably excludes excess levels of dabigatran, but does not rule out typical on-therapy drug concentrations. The PT is insufficiently sensitive to dabigatran to be useful in most situations. Factor Xa inhibitors may be quantified with an anti-Xa assay calibrated with drug-specific standards. A normal PT probably excludes excess levels of rivaroxaban and edoxaban, but not typical on-therapy levels of these agents. The PT is less sensitive to apixaban. Depending on the sensitivity of the thromboplastin reagent, a normal PT may not exclude excess levels of apixaban. The APTT has inadequate sensitivity to factor Xa inhibitors and is not recommended for their measurement.
Thrombotic thrombocytopenia purpura (TTP) is a rare, life-threatening disease with an incidence of approximately 2 persons per million per year. It is characterized by severe deficiency of the von ...Willebrand cleaving protease, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), leading to formation of platelet-rich thrombi in the microvasculature. Prompt initiation of appropriate therapy, particularly plasma exchange, may be life-saving. Diagnosis of TTP is challenging because of its diverse clinical manifestations, overlap in clinical presentation with other thrombotic microangiopathies, and limited availability of ADAMTS13 testing. Clinical prediction scores have been developed to estimate the pretest probability of severe ADAMTS13 deficiency and may be used as an adjunct to clinical judgment to guide initial management decisions. An ADAMTS13 activity level of less than 10% supports the diagnosis of TTP in appropriate clinical contexts, but many centers do not offer testing in-house and must send out the test to a reference laboratory with a turnaround time of several days. In such instances, initial management decisions must be made without the benefit of laboratory testing. In patients with TTP, inhibitor tests may be useful for distinguishing immune-mediated from congenital TTP. In this article, we review the epidemiology, natural history, and clinical presentation of TTP and laboratory assays for TTP including ADAMTS13 activity and inhibitor assays. We also describe an evidence-based approach to the evaluation of a patient with suspected TTP that integrates clinical and laboratory assessment.
Background Direct oral anticoagulants (DOACs) are the treatment of choice for most patients with atrial fibrillation and/or noncancer-associated venous thromboembolic disease. Although routine ...monitoring of these agents is not required, assessment of anticoagulant effect may be desirable in special situations. The objective of this review was to summarize systematically evidence regarding laboratory assessment of the anticoagulant effects of dabigatran, rivaroxaban, apixaban, and edoxaban. Methods PubMed, Embase, and Web of Science were searched for studies reporting relationships between drug levels and coagulation assay results. Results We identified 109 eligible studies: 35 for dabigatran, 50 for rivaroxaban, 11 for apixaban, and 13 for edoxaban. The performance of standard anticoagulation tests varied across DOACs and reagents; most assays, showed insufficient correlation to provide a reliable assessment of DOAC effects. Dilute thrombin time (TT) assays demonstrated linear correlation ( r2 = 0.67-0.99) across a range of expected concentrations of dabigatran, as did ecarin-based assays. Calibrated anti-Xa assays demonstrated linear correlation ( r2 = 0.78-1.00) across a wide range of concentrations for rivaroxaban, apixaban, and edoxaban. Conclusions An ideal test, offering both accuracy and precision for measurement of any DOAC is not widely available. We recommend a dilute TT or ecarin-based assay for assessment of the anticoagulant effect of dabigatran and anti-Xa assays with drug-specific calibrators for direct Xa inhibitors. In the absence of these tests, TT or APTT is recommended over PT/INR for assessment of dabigatran, and PT/INR is recommended over APTT for detection of factor Xa inhibitors. Time since last dose, the presence or absence of drug interactions, and renal and hepatic function should impact clinical estimates of anticoagulant effect in a patient for whom laboratory test results are not available.
Abstract Background Non–vitamin K oral anticoagulants (NOACs) do not require routine laboratory monitoring. However, laboratory measurement may be desirable in special situations and populations. ...Objectives This study’s objective was to systematically review and summarize current evidence regarding laboratory measurement of the anticoagulant activity of dabigatran, rivaroxaban, and apixaban. Methods We searched PubMed and Web of Science for studies that reported a relationship between drug levels of dabigatran, rivaroxaban, and apixaban and coagulation assay results. Study quality was evaluated using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2). Results We identified 17 eligible studies for dabigatran, 15 for rivaroxaban, and 4 for apixaban. For dabigatran, a normal thrombin time excludes clinically relevant drug concentrations. The activated partial thromboplastin time (APTT) and prothrombin time (PT) are less sensitive and may be normal at trough drug levels. The dilute thrombin time (R2 = 0.92 to 0.99) and ecarin-based assays (R2 = 0.92 to 1.00) show excellent linearity across on-therapy drug concentrations and may be used for drug quantification. For rivaroxaban and apixaban, anti-Xa activity is linear (R2 = 0.89 to 1.00) over a wide range of drug levels and may be used for drug quantification. Undetectable anti-Xa activity likely excludes clinically relevant drug concentrations. The PT is less sensitive (especially for apixaban); a normal PT may not exclude clinically relevant levels. The APTT demonstrates insufficient sensitivity and linearity for quantification. Conclusions Dabigatran, rivaroxaban, and apixaban exhibit variable effects on coagulation assays. Understanding these effects facilitates interpretation of test results in NOAC-treated patients. More information on the relationship between drug levels and clinical outcomes is needed.
This article summarizes our approach to the management of children and adults with primary immune thrombocytopenia (ITP) who do not respond to, cannot tolerate, or are unwilling to undergo ...splenectomy. We begin with a critical reassessment of the diagnosis and a deliberate attempt to exclude nonautoimmune causes of thrombocytopenia and secondary ITP. For patients in whom the diagnosis is affirmed, we consider observation without treatment. Observation is appropriate for most asymptomatic patients with a platelet count of 20 to 30 × 109/L or higher. We use a tiered approach to treat patients who require therapy to increase the platelet count. Tier 1 options (rituximab, thrombopoietin receptor agonists, low-dose corticosteroids) have a relatively favorable therapeutic index. We exhaust all Tier 1 options before proceeding to Tier 2, which comprises a host of immunosuppressive agents with relatively lower response rates and/or greater toxicity. We often prescribe Tier 2 drugs not alone but in combination with a Tier 1 or a second Tier 2 drug with a different mechanism of action. We reserve Tier 3 strategies, which are of uncertain benefit and/or high toxicity with little supporting evidence, for the rare patient with serious bleeding who does not respond to Tier 1 and Tier 2 therapies.
Edoxaban, an oral direct inhibitor of factor Xa, was recently approved in the United States and Japan for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation ...and for treatment of venous thromboembolism (VTE). It is also licensed in Japan for prevention of VTE after major orthopedic surgery. Although routine laboratory monitoring of edoxaban is not required, laboratory measurement may be desirable in special circumstances. Our objective was to provide a systematic review of current evidence on laboratory measurement of the anticoagulant activity of edoxaban. PubMed and the Cochrane Library were searched for studies that reported a relationship between coagulation tests and plasma edoxaban levels. Study quality was assessed using Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). We identified 9 eligible studies. Anti-Xa activity is linear across a broad range of drug levels (
R
2
> 0.95) and may be used for edoxaban quantification. The assay shows greater variability at above on-therapy drug concentrations. The PT is less sensitive to edoxaban. A normal prothrombin time may not exclude clinically relevant on-therapy drug levels. The activated partial thromboplastin time has insufficient sensitivity to edoxaban for measurement of its anticoagulant activity. Edoxaban exhibits variable effects on coagulation assays. Understanding these effects facilitates interpretation of test results in edoxaban-treated patients. More data on the relationship between drug levels, coagulation test results, and clinical outcomes in patients are needed.
The thrombopoietic growth factors (TGFs) are a novel class of compounds for the treatment of chronic immune thrombocytopenia (ITP). The first of these agents to receive regulatory approval, ...romiplostim and eltrombopag, have demonstrated impressive efficacy and tolerability in randomized controlled trials and open-label extension studies of several years duration and stand poised to revolutionize the management of ITP. Nonetheless, critical questions regarding the safety of these agents, particularly after long-term administration, remain partially unanswered. The objective of this review is to describe the reported and potential toxicities of the TGFs, including bone marrow fibrosis, thrombosis, rebound thrombocytopenia, hematologic malignancy, neutralizing antibody formation, hepatotoxicity, cataract formation, and common adverse events. The incidence and clinical implications of these toxicities as well as strategies for patient safety monitoring are examined.
Although the direct oral anticoagulants (DOACs) do not require routine monitoring and reduce bleeding compared with warfarin, there are special circumstances in which laboratory measurement or ...reversal of their anticoagulant effect may be indicated. The dilute thrombin time and ecarin-based assays are able to quantify dabigatran across a broad range of concentrations, but are not widely available. A normal thrombin time excludes clinically relevant levels and a normal activated partial thromboplastin time probably excludes excess levels of dabigatran. Factor Xa inhibitors may be quantified with an anti-Xa assay calibrated with drug-specific standards. A normal prothrombin time probably excludes excess levels of rivaroxaban and edoxaban, but not apixaban. Patients with minor and moderate DOAC-associated bleeding can be treated with supportive care and general hemostatic measures. Nonspecific reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate) are of unproven benefit, carry a risk of thrombosis, and should be reserved for severe bleeding. Specific reversal agents, such as idarucizumab (a monoclonal antibody fragment that binds dabigatran) and andexanet alfa (a recombinant factor Xa variant that binds factor Xa inhibitors but lacks coagulant activity), are in clinical development.
Coronavirus disease 2019 (COVID-19) is a viral infection that can, in severe cases, result in cytokine storm, systemic inflammatory response and coagulopathy that is prognostic of poor outcomes. ...While some, but not all, laboratory findings appear similar to sepsis-associated disseminated intravascular coagulopathy (DIC), COVID-19- induced coagulopathy (CIC) appears to be more prothrombotic than hemorrhagic. It has been postulated that CIC may be an uncontrolled immunothrombotic response to COVID-19, and there is growing evidence of venous and arterial thromboembolic events in these critically ill patients. Clinicians around the globe are challenged with rapidly identifying reasonable diagnostic, monitoring and anticoagulant strategies to safely and effectively manage these patients. Thoughtful use of proven, evidence-based approaches must be carefully balanced with integration of rapidly emerging evidence and growing experience. The goal of this document is to provide guidance from the Anticoagulation Forum, a North American organization of anticoagulation providers, regarding use of anticoagulant therapies in patients with COVID-19. We discuss in-hospital and post-discharge venous thromboembolism (VTE) prevention, treatment of suspected but unconfirmed VTE, laboratory monitoring of COVID-19, associated anticoagulant therapies, and essential elements for optimized transitions of care specific to patients with COVID-19.
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