CHAPTER 2-78: HEPARINS

INTRODUCTION

Heparins (Table II–32) have been used for many years as injectable anticoagulants for prophylaxis of thromboembolic disease and management of multiple conditions including hypercoagulable disorders, venous thromboembolic disease, acute coronary syndrome, and to maintain patency in intravascular access and hemodialysis machines. Conventional or unfractionated heparin (UFH) is primarily administered in health care settings and thus intentional overdoses are rare; most cases involve inadvertent iatrogenic administration errors. Low–molecular-weight-heparins (LMWHs) are obtained from UFH and have greater bioavailability, longer half-life, predictable anticoagulation with a fixed-dose schedule, and are more easily self-administered by patients in outpatient settings.

MECHANISM OF TOXICITY

1. UFH causes anticoagulation by binding to and activating antithrombin III, which then inactivates thrombin (factor II) and other proteases involved in coagulation, including factors IX, Xa, XI, XII, kallikrein, and thrombin.

2. LMWHs act similar to UFH, but exhibit greater factor Xa inhibition and less inhibition of thrombin.

3. Heparins do not cross the placenta and have been used during pregnancy to treat hypercoagulable states, thromboembolic disease, and to prevent miscarriage in patients with recurrent fetal loss.

4. Pharmacokinetics

   1. UFH remains largely in the intravascular compartment (Vd 0.06 L/kg) bound to proteins and fibrinogen. Elimination half-life is dose-dependent and ranges from 1 to 2.5 hours. Elimination is largely hepatic via a heparinase enzyme.

   2. LMWHs have high bioavailability (90%) when administered via the subcutaneous route. Elimination half-life ranges from 3 to 6 hours depending on the specific preparation. Peak anticoagulant effect occurs between 3 and 5 hours after administration. LMWHs are hepatically metabolized and renally eliminated. (See also Table II–66).

TOXIC DOSE

1. The toxic dose is highly variable and depends on several patient-dependent and administration factors. Any patient receiving anticoagulation therapy is at risk for bleeding, even at therapeutic doses.

2. Patients at increased risk for bleeding include those receiving warfarins or other newer anticoagulants, antiplatelet agents, nonsteroidal anti-inflammatory drugs, and (with LMWHs) patients taking selective serotonin reuptake inhibitors. Patients with renal insufficiency are at increased risk of LMWH toxicity.

CLINICAL PRESENTATION

1. After acute exposure, anticoagulant effects may be subclinical in nature. However, significant bleeding may occur. Reported complications have included abdominal wall and other subcutaneous hematomas, intrahepatic hemorrhage, gastrointestinal hemorrhage, spinal hematoma, post-traumatic compartment syndrome, and intracranial hemorrhage. Fatalities are rare but have been reported.

2. In addition to bleeding complications, chronic exposure to heparin infrequently ...