Heparin

Overview

Heparins are a class of anticoagulant polysaccharides that bind to Antithrombin III and potently enhance its inhibitory effect on activated thrombin and Factor X. As a consequence, heparins serve as powerful anticoagulants. Two basic classes of heparins have been generated. The original class, Unfractionated Heparin (UFH), is a crude mixture of variable length polysaccharides derived from porcine intestinal mucosa. Newer classes, known as Low Molecular Weight Heparin (LMWH), are derived by purification of the smaller molecules within UFH. UFH and LMWH display slightly distinct pharmacological properties that yield different pharmacokinetics and anticoagulation profiles.

Mechanism of Action

As mentioned, heparins potently enhance the enzymatic activity of Antithrombin III which serves to inhibit activated Thrombin and Factor X (See: Coagulation for a review of the actions of antithrombins). This level of knowledge is sufficient for most medical students; however, for the sake of interest we delve slightly deeper below.
The mechanisms by which heparins promote antithrombin-mediated inactivation of Factor X and Thrombin are distinct. In the case of Factor X, binding of heparins to Antithrombin III appears to directly activate antithrombin's enzymatic activity against Factor X. In contrast, the promotion of antithrombin-mediated inactivation of thrombin appears to occur solely by the ability of large heparin molecules to physically bind both heparin and thrombin, bringing them into close proximity to one another. Importantly, only large molecular weight species of heparins can perform this function and these are only found in UFH and are absent in LMWH. Consequently, while UFH promotes antithrombin-mediated inactivation of both Factor X and Thrombin, LMWH promotes anti-thrombin mediated inactivation of solely thrombin.

Laboratory Monitoring of Anticoagulation

The clinical effect of UFH can be monitored by trending the PTT while the PT is affected to a much lesser extent. Frequent monitoring of the PTT is necessary during IV administration of UFH as it can swing wildly high during up-titration of UFH. Therapeutic doses are considered 1.5 to 2 fold that of the normal value of PTT. In contrast, LMWH cannot be monitored by assessing the PTT; however, because of its much more predictable effect on coagulation, laboratory monitoring of coagulation parameters is not necessary.

Pharmacokinetics

Both UFH and LMWH must be administered parenterally; however these drugs display a number of distinct pharmacokinetic properties that make them useful in different clinical settings. The anticoagulant effect of UFH has a much quicker onset and has a shorter half-life, making it ideal for acute unstable situations which require fast-on times and potentially fast-off times. In contrast, the anticoagulant effect of LMWHs are of slower offset with much longer half-lives, making them ideal for stable or outpatient scenarios.

Reversal

The anticoagulant effects of UFH can be rapidly neutralized with the administration of Protamine Sulfate, a crude mixture of polypeptides derived from salmon sperm that bind and thus inactivate negatively charged heparin residues. However, protamine sulfate only binds to long heparin chains and is thus ineffective against LMWH.

Adverse Effects

The most common adverse reaction is bleeding; however, the most feared complication of heparin therapy is that of Heparin-induced Thrombocytopenia which occurs in 2-5% of patients receiving this drug.

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