External Quality Assessment for Unfractionated Heparin Monitoring: An Update from Australasia/Asia-Pacific.

The Heparin Anti-Xa Therapeutic Range: Are We There Yet?

Intravenous unfractionated heparin (UFH) remains an important therapeutic agent, particularly in the inpatient setting, for anticoagulation. Historically, the activated partial thromboplastin time (aPTT) has been the primary laboratory test used to monitor and adjust UFH. The aPTT test has evolved since the 1950s, and the historical goal range of 1.5-2.5 times the control aPTT, which first gained favor in the 1970s, has fallen out of favor due to a high degree of variability in aPTT readings from one laboratory to another, and even from one reagent to another. As a result, it is now recommended that the aPTT goal range be based on a corresponding heparin concentration of 0.2-0.4unit/ml by protamine titration or 0.3-0.7unit/ml by antifactor Xa assay. Given that several biologic factors can influence the aPTT independent of the effects of UFH, many institutions have transitioned to monitoring heparin with antifactor Xa levels, rather than the aPTT. Clinical data from the last 10-20years have begun to show that a conversion from aPTT to antifactor Xa monitoring may offer a smoother dose-response curve, such that levels remain more stable, requiring fewer blood samples and dosage adjustments. Given the minimal increased acquisition cost of the antifactor Xa reagents, it can be argued that the antifactor Xa is a cost-effective method for monitoring UFH. In this review, we discuss the relative advantages and disadvantages of the aPTT, antifactor Xa, and protamine titration tests, and provide a clinical framework to guide practitioners who are seeking to optimize UFH monitoring within their own institutions.

Activated partial thromboplastin time overestimates anti-coagulation in left ventricular assist device patients

Unfractionated heparin (UFH) has a complex pharmacologic profile that necessitates patient monitoring to prevent inadequate anticoagulation or overdosage and hemorrhage. Factor Xa inhibitory assays (to measure anti-Xa activity) are used to adjust UFH dosage and define safe and effective regimens for specific thrombotic disorders in humans. In this study, the accuracy, linearity, and clinical utility of a chromogenic assay were assessed for monitoring UFH anti-Xa activity in canine plasma samples. A commercial assay (Rotachrom Heparin, Diagnostica Stago, Parsippany, NJ, USA) was used to measure anti-Xa activity in canine plasma samples spiked with different concentrations of UFH. Background absorbance and assay linearity were compared for canine and human plasmas. Percentage recovery of UFH anti-Xa activity and intra- and interassay imprecisions were investigated by multiple measurements of canine plasma to which known amounts of UFH were added. The spiked plasma samples also were used to determine the heparin sensitivity of an activated partial thromboplastin time (aPTT) test. Canine plasma samples were assayed at a higher dilution than were human plasma samples (3:8 versus 4:8) to eliminate higher background anti-Xa activity in canine plasma. Using this modification, the recovery of anti-Xa activity in canine plasma was linear (R2 > .9) at concentrations of 0 - 0.75 U/mL UFH. Intra- and interassay imprecisions for plasma samples containing 0.5 U/mL UFH were <10%, whereas samples containing 0.25 U/mL UFH had imprecisions of 13% and 24%, respectively. The anti-Xa activity range of 0.5 - 0.75 U/mL caused prolongation of aPTTs to 1.5 - 2.5 times the assay mean. Plasma anti-Xa activity of dogs treated with UFH can be accurately monitored using this commercially available chromogenic assay.

91-Year-Old Man With Upper Extremity Ecchymoses

Monitoring unfractionated heparin therapy. 4 hour-stability of anti-Xa activity in unspun citrated tubes

Lack of Inter-Laboratory Agreement in the Monitoring of Unfractionated Heparin Using the Anti-Factor Xa Activity and the Anti-Factor Xa-Correlated Activated Partial Thromboplastin Time

Direct oral anticoagulants (DOACs), including direct thrombin inhibitors (dabigatran) and direct factor Xa inhibitors (apixaban, rivaroxaban, edoxaban), have transformed anticoagulant management in recent years due to their predictable pharmacodynamics, rapid onset of action, and fixed dosing without the need for routine laboratory monitoring. Unfractionated heparin (UFH) remains the anticoagulant of choice for patients who are acutely unwell and treated in intensive care units due to its short half-life, reversibility, ease of dose titration, and nonrenal dependent excretion. It is therefore not uncommon for an individual's anticoagulation management to require rapid changing from DOAC to UFH. Due to UFH's complex pharmacokinetics, including nonspecific binding to acute phase proteins and dose-dependent clearance, careful laboratory monitoring, generally with activated partial thromboplastin time (APTT) or anti-factor Xa (anti-Xa) activity, is necessary. When transitioning from a DOAC to UFH, overlapping pharmacologic effects can significantly interfere with coagulation assays, particularly if residual DOAC levels persist at the time UFH is initiated. DOACs can prolong the APTT and elevate anti-Xa activity, leading to overestimation of UFH activity, inappropriate dose adjustments, and increased risk of bleeding or thromboembolic events. Here, we examine the laboratory implications of transitioning from DOAC therapy to UFH, with a focus on the performance and interpretation of APTT and anti-Xa assays in the presence of residual DOAC levels and how to overcome the interference of DOAC in UFH monitoring. We suggest an algorithm to follow during this transition.

Activated clotting time (ACT) is used in cardiac surgery for monitoring unfractionated heparin (UFH). In endovascular radiology, ACT use is less established. We aimed to test the validity of ACT in UFH monitoring in endovascular radiology. We recruited 15 patients undergoing endovascular radiologic procedure. ACT was measured with ICT Hemochron® device as point-of-care (1) before standard UFH bolus, (2) immediately after the bolus, and in some cases (3) 1 h into the procedure or a combination thereof (altogether 32 measurements). A total of two different cuvettes, ACT-LR and ACT+ were tested. A reference method of chromogenic anti-Xa was used. Blood count, APTT, thrombin time and antithrombin activity were also measured. UFH levels (anti-Xa) varied between 0.3–2.1 IU/mL (median 0.8) and correlated with ACT-LR moderately (R2 = 0.73). The corresponding ACT-LR values were 146–337 s (median 214). ACT-LR and ACT+ measurements correlated only modestly with one another at this lower UFH level, with ACT-LR being more sensitive. Thrombin time and APTT were unmeasurably high after the UFH dose, rendering them of limited use in this indication. We adopted an ACT target of >200–250 s in endovascular radiology based on this study. While ACT correlation with anti-Xa is suboptimal, the readily available point-of-care nature increases its suitability.

There is uncertainty as to which activities of unfractionated heparin (UFH) and low MW heparin are responsible for their anticoagulant and antithrombotic properties. We have sought to answer this question by examining plasma samples taken during a recently conducted dose-finding study of the low MW heparin, CY222, in haemodialysis for chronic renal failure. In this study, in vivo anticoagulant effect was assessed by measurement of plasma FPA levels. UFH was administered as a dose of 5000 iu bolus + 1,500 iu/h maintenance infusion, while the effects of three doses of CY222 were studied (10,000, 15,000 and 20,000 Institute Choay anti-factor Xa u bolus, all with 1,500 Institute Choay anti-factor Xa u/h maintenance infusion). Anti-factor Xa levels were determined by chromogenic substrate assay. Anti-thrombin levels were determined by chromogenic substrate assay and by quantitation of catalysed thrombin-inhibitor complexes (using autoradiography). Analysis of the results indicate that plasma fibrinopeptide A (FPA) levels correlate with anti-factor Xa (r = -0.45) and anti-thrombin (substrate) (r = -0.63) levels of UFH, but only with the anti-factor Xa levels (r = -0.41) of CY222. These results suggest that the anti-factor Xa assay is currently the most suitable assay for monitoring low MW heparins such as CY222 in humans.

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Increased Mortality and Bleeding in a Large Cohort of Patients on Heparin Anticoagulation Therapy with Discordant Anti-Factor Xa Activity and Activated Partial Thromboplastin Time (PTT); Implications for Clinical Management

This report compares the pharmacokinetics and the bioavailabilities of the antifactor Xa and of the antifactor IIa activities generated by intravenous (IV) and subcutaneous (SC) injections of increasing doses of unfractionated heparin (UH) and of a low molecular weight heparin (CY 216). Rabbits were injected with 500, 1,000, 2,500, and 5,000 antifactor Xa u/kg of both heparins and their biological activities were followed at various time intervals. After IV injection the clearance of the antifactor Xa activities was independent of the dose and the clearance of UH was significantly higher than that of CY 216; after SC injection the bioavailability estimated from the antifactor Xa effect was consistently over 100% for CY 216 while that of UH increased from 27% at the lowest dose to 93% at the highest dose. The pharmacokinetic parameters estimated by the antifactor IIa activity of UH were superimposable to those calculated with the antifactor Xa activity. For CY 216 no direct comparison between the two activities was made since the dose injected expressed in antifactor IIa units was 3.4 times lower. UH and CY 216 were therefore injected intravenously to other animals at equivalent and increasing doses expressed in antifactor IIa units (50-5,000 u/kg). The pharmacokinetic parameters calculated from the curves of the antifactor IIa activities were basically identical except at the two lower doses (50 and 100 u/kg) for which UH was cleared faster than CY 216.(ABSTRACT TRUNCATED AT 250 WORDS)

In haemodialysis low-molecular-weight (LMW) heparin is increasingly used for anticoagulation. The advantages over unfractionated (UF) heparin are the lower bleeding risk and the lack of influence on lipid metabolism. However, no reliable and rapid method is available so far to control the efficacy and safety of LMW heparin during haemodialysis. The specific anti-factor Xa (aXa) chromogenic substrate assays are laborious and time consuming. In the present study we have compared chromogenic assay with a coagulation assay (heptest), which was performed from plasma and whole-blood samples. The effects were compared with unfractionated heparin during haemodialysis. The aXa activity in the chromogenic S2222 assay ranged between 0.2 and 0.5 U/ml with UF heparin and between 0.4 and 0.8 U/ml with LMW heparin during haemodialysis. The coagulometric aXa activity in heptest assay from plasma was 0.6-1.0 U/ml with UF heparin and 1.2-2.0 U/ml with LMW heparin. The Heptest coagulation values from citrated whole blood samples ranged from 0.4 to 0.8 U/ml with UF heparin and from 0.8 to 1.4 U/ml with LMW heparin. The prolongation of the heptest clotting times with UF and LMW heparin was in the range of 4.4 for UF heparin and 5.2 for LMW heparin using the whole-blood assay. Heptest assay from plasma samples yielded prolongations of 6.1 with UF heparin and 6.6 with LMW heparin. The data show that the coagulation assay is rapid and reproducible using plasma or uncentrifuged whole-blood samples and is valid to monitor UF heparin or LMW heparin in patients undergoing chronic intermittent haemodialysis.

Monitoring of unfractionated heparin with rotational thrombelastometry using the prothrombinase-induced clotting time reagent (PiCT®)