Unfractionated Heparin and Other Antithrombin Mediated Anticoagulants

Clinical Laboratory Science, Spring 2004 by Adler, Brian K

ABBREVIATIONS: LMWH = low-molecular-weight heparins; PTT = partial thromboplastin time; TFPI = tissue factor pathway inhibitor; UFH = unfractionated heparin.

INDEX TERMS: coagulation; heparin.

Clin Lab Sci 2004;17(2):113

Several anticoagulants work by enhancing the role of antithrombin (previously called antithrombin III). The group includes one of the oldest anticoagulants, unfractionated heparin (UFH), along with the more recent low-molecular-weight heparins (LMWH), heparinoids, i.e., Danaparoid® that has been removed from the market, and the synthetic drugs fondaparinux and idraparinux, currently in clinical trials. All of these agents work indirectly to inhibit the generation of thrombin and fibrin. They work by binding to antithrombin, creating a marked increase in the affinity of antithrombin for the serine protease active site of the coagulation factor(s) to inhibit their activity. While these drugs share this mechanism of action, the drugs differ in the coagulation factors most targeted for inactivation. Moreover, they differ in their pharmacologic properties leading to significant differences with regard to predictability and flexibility of dosing and administration, as well as toxicity profiles (Table 1).

UNFRACTIONATED HEPARIN

UFH has a long history of clinical benefit for both arterial and venous thrombotic diseases. Despite the advent of newer agents, it still plays an important role in the care of diverse groups of patients and disorders. The familiarity and reversibility of UFH give it some clear advantages. Nonetheless, it also presents some definite shortcomings, especially with regard to monitoring needs and potential for severe complications.

UFH consists of heterogeneous-length polysaccharides with sugar subunits having variable sulfation. Molecular weights of individual molecules vary between 3,000 and 30,000 daltons.1,2 Only about one-third of the administered UFH will have the required specific pentamer sequence that has high affinity for antithrombin and provides the anticoagulant activity. Upon binding to this sequence, antithrombin takes on a new conformation with approximately a 1000-fold increase in its ability to inhibit the serine protease active site of coagulation factors. Thrombin (factor IIa) and factor Xa have the greatest sensitivity to the heparin-antithrombin complex. However, inhibition of thrombin requires polysaccharide molecules of at least 18 units while heparin molecules that contain no more than the specific pentamer sequence can only inhibit factor Xa. Most preparations of UFH give about equal inhibition of these two factors (IIa and Xa).

UFH requires either intravenous or subcutaneous administration. The latter has an associated one to two hour delay in its anticoagulant effect. The rate of clearance for heparin varies inversely according to the molecular length. Thus, the relative levels of factor Xa and thrombin inhibition vary over time. Additional factors that confound predictability of dose effect include heparin binding to plasma proteins and cells such as macrophages and endothelial cells. These cells will also depolymerize the heparin, which is a saturable phase of its clearance. The renal phase is slower and not saturable. This combination of variable protein binding and clearances creates a nonlinear relationship between the antithrombotic effect and heparin dose in the therapeutic range.3

Although dose and effect lack a linear relationship, the heparin dose does have a relationship to both efficacy and safety. Thus, monitoring plays a critical role in UFH therapy. Older studies have used a simple activated partial thromboplastin time (PTT) with therapeutic range generally being defined as a ratio of 1.5 to 2.5, patient to control. However, this approach has limitations as it emphasizes the antithrombin activity since factor Xa inhibition has little effect on this assay. In addition, the heparin sensitivity of different available PTT reagents varies.4 Thus, the best approach standardizes the PTT using either heparin concentration or factor Xa inhibition level.1 The heparin concentration method sets the therapeutic PTT range to correspond to heparin levels between 0.2 to 0.4 U/mL as determined by protamine titration, and the Xa inhibition method uses a range that corresponds to an anti-Xa level of 0.3 to 0.7 U/mL. Initial monitoring should begin about six hours after the initial bolus dose.

UFH has found use in a wide variety of clinical situations that involve both venous and arterial thromboses. Elucidation of the broad applications for UFH goes beyond the scope of this short review, but may be found in other recent reviews.2,5 In addition to the familiarity and proven efficacy, UFH enjoys the advantage of being completely reversible. Protamine sulfate can reverse the heparin effect with 1 mg protamine neutralizing about 90 mg of heparin.

Despite the great success of unfractionated heparin, it has significant limitations. First, a high propensity for protein and cell surface binding limits and causes variability in anticoagulant effect with a resulting need for frequent monitoring. Second, the size of the heparin-antithrombin complex prevents it from inhibiting either the factor Xa in the prothrombinase complex or the thrombin attached to fibrin. Third, long term heparin therapy causes osteopenia.2 Fourth, heparin induced thrombocytopenia (HIT) can occur due to the development of antibodies directed against a complex of heparin and platelet factor 4 (PF4).6 These antibodies have the ability to activate platelets and cause both venous and arterial thromboses that have been associated with a significant mortality rate.