Heparins are glycosaminoglycans particularly rich in sulfuric groups with anticoagulant activity and used for the prevention and treatment of venous and arterial thromboembolic disease. Based on molecular weight, heparins are divided into two classes: unfractionated heparin (ENF), with a molecular weight between 3000 and 30,000 Da, and low molecular weight heparin (EBPM), with a molecular weight between 4000 and 6000 Da.
The anticoagulant activity of ENF is mediated by the pentasaccharide sequence that binds to antithrombin and, through this, exerts its inhibitory action, in an irreversible manner, on FXa and FIIa of the coagulation cascade (Fig. 1). ENF bound to antithrombin also inhibits, to a lesser extent, FIXa, FXIa, and FXIIa. To exert inhibitory action on thrombin (FIIa), heparin molecules must contain more than 18 saccharide units. Molecules with less than 18 saccharide units, such as EBPMs and the synthetic pentasaccharide fondaparinux, are not able to bind and inhibit FIIa, only FXa.
Fig1. Action of anticoagulant drugs. (Copyright EDISES 2021. Reproduced with permission)
ENF is of extractive origin (from bovine lung and pig intestine) and is administered subcutaneously or intravenously, as it is not absorbed orally. Because of the wide variability in anticoagulant effects, ENF requires laboratory monitoring, via the aPTT, to ensure appropriate doses. The half-life of ENF varies from 30 to 150 minutes, depending on the doses administered. ENF is eliminated by two mechanisms: a saturable one, by hepatic macrophages and endothelial cells, and a nonsaturable one, slower, mainly renal. At therapeutic doses, a large percentage of heparin is eliminated through the rapid dose-dependent saturable pathway, and only for very high doses of ENF, when hepatic clearance is saturated, the elimination is renal. Therefore, ENF can also be used in patients with severe renal impairment. The antidote is protamine sulfate. A rare but serious complication of ENF use is the occurrence of heparin-induced thrombocytopenia (HIT) due to the formation of anti-FP4 antibodies.
EBPMs are derived from the fractionation, by chemical or enzymatic methods, of ENF. EBPM molecules contain less than 13 saccharide units (in addition to the pentasaccharide structure), so their inhibitory effect, mediated by binding with antithrombin, is mainly towards FXa. EBPMs have several advantages over ENF: longer half-life (3–6 h), which allows for single or dual daily subcutaneous administration; higher bioavailability (~90%); lower incidence of bleeding; greater predictability of the dose–response relationship; and lower incidence of HIT. They are administered at fixed dos ages based on body weight. When used in therapeutic regimens, they do not require laboratory monitoring to evaluate the anticoagulant effect, except in some clinical conditions (renal insufficiency, obese patients, and pediatric patients). In these cases, laboratory monitoring is performed through the dosage of anti-FXa activity. On the other hand, weekly platelet count monitoring is necessary for the first 2 weeks of administration due to the possible, albeit very rare, occurrence of HIT. Elimination is mainly renal, so in patients with renal insufficiency, it is preferable to administer ENF or reduce the prophylactic or therapeutic dose of EBPM.
Fondaparinux is an entirely synthetic product consisting of five saccharide units (molecular weight of 1728 Da), which exerts its anticoagulant activity exclusively towards FXa through the strong link with antithrombin. The drug, administered subcutaneously, is highly bioavailable, has a plasma half-life of about 17 h, and is eliminated unmodified by the renal route (it is therefore contraindicated in patients with renal insufficiency). These characteristics allow for a single daily administration and a rapid onset of antithrombotic activity. Like EBPM, it does not require laboratory monitoring.
