Challenges in Variation and Responsiveness of Unfractionated Heparin

Abstract

Unfractionated heparin (UFH) has been in clinical use for more than half a century. Despite its undoubted contribution to the treatment and prevention of thrombosis, heparin is significantly limited by its variable biochemical composition and unpredictable pharmacokinetics. The situation is compounded by the fact that methods for monitoring heparin do not necessarily reflect its therapeutic effect. The activated partial thromboplastin time (aPTT) is a method for monitoring heparin therapy that is simple, cheap, and readily available. However, it is also poorly standardized and is affected by numerous factors-both analytic and preanalytic-that are unrelated to the heparin effect. Establishing an appropriate therapeutic range for the aPTT is challenging for smaller clinical laboratories, and the antifactor Xa method of measuring heparin levels is not widely available. The College of American Pathologists published consensus guidelines in an effort to improve the laboratory monitoring of UFH therapy. However, it seems unlikely that the laboratory problems associated with monitoring UFH will be resolved. Unfractionated heparin is highly antigenic and carries a significant risk of heparin-induced thrombocytopenia (HIT). Even in the absence of thrombocytopenia or thrombosis, the presence of heparin-associated antibodies may predict adverse clinical outcomes and strengthen the rationale for the ultimate replacement of UFH. Fortunately, alternatives to UFH, such as low-molecular-weight heparins, direct thrombin inhibitors, and more specific factor Xa inhibitors, are becoming available for clinical use. The pharmacokinetics of these agents are more predictable and rely much less on laboratory monitoring. Nonheparin agents also eliminate the risk of HIT. The emergence of these newer anticoagulants makes the continued use of UFH increasingly difficult to justify.

The Optimum Number and Types of Plasma Samples Necessary for an Accurate Activated Partial Thromboplastin Time–Based Heparin Therapeutic Range

“…[4][5][6]12,18 The most commonly performed method is the ex vivo HTR determination described in several guideline publications. 4,7 Since the HTR method itself creates imprecision, using a standard set of parameters will significantly increase the precision and accuracy of the HTR.…”

“…4,7 The aPTT-based HTR is only a guideline for monitoring UFH therapy in patients. [3][4][5][6] The standard acceptable HTR determination method (based on College of American Pathologists [CAP] and CLSI guidelines) is the ex vivo UFH plasma method. 4,7,20 Both the CAP and CLSI guidelines make only general recommendations.…”

“…The fixed-range methods (arbitrary fixed values or ratio-based ranges) and the in vitro or ''spiked curve'' method are not accurate for all reagents. [4][5][6] The cumulative summary method has been the recommended method but relies on the previous range and small statistical variation of the new reagent compared to the old reagent. 4,7 Finally, the ex vivo method compares the aPTT and heparin level in the plasma of patients receiving UFH.…”

“…The causes of variation include (1) differences in the heparin sources (preparation and content), (2) biological variation (heparin binding proteins, coagulation factor levels, and in vivo heparin processing), (3) clinical parameters (international normalized ratio [INR] and optimum clinical concentration), (4) preanalytic variation (sample collection, processing, and storage), and (5) analytic variables (different aPTT reagent sensitivities, components, and concentrations). [4][5][6][7]10,11 Based on these issues, aPTT monitoring of UFH is difficult to standardize even using the ex vivo HTR method. 4,7,8 Many factors can influence both aPTT and heparin values.…”

Changes in the USP Heparin Monograph and Implications for Clinicians

“…12,13 Despite the numerous analytic and nonanalytic factors known to significantly influence the aPTT, this test is used most often for monitoring heparin infusion therapy. 11,14,15 To reduce the impact of aPTT variability, the College of American Pathologists (CAP) and the ACCP recommend that the heparin aPTT target range be equivalent to a therapeutic heparin level by antifactor Xa analysis (0.3-0.7 units/ml for venous thromboembolism [VTE]). 9,16 To accomplish this, paired samples (aPTT and heparin antifactor Xa level) are obtained from patients receiving heparin.…”