Heparins (Table II-30) 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.

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-63).

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 direct oral 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.

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 predisposes patients to necrotic skin lesions, aldosterone suppression leading to hyperkalemia, and osteoporosis.
3. Heparin-induced thrombocytopenia (HIT) is an uncommon but potentially serious complication of therapeutic use of heparins. It is more common with UFH but can occur with LMWH.
   1. Type 1 HIT occurs in the first few days after heparin is started and usually normalizes with continued heparin administration.
   2. Type 2 HIT is less common but more serious. It occurs 4-10 days after starting heparin, is immune-mediated and may include thrombosis as well as bleeding (HIT with thrombosis, or HITT). It is more common in females, nonwhites, and the elderly.
   3. Treatment includes discontinuation of heparin products and use of alternative anticoagulants.

1. Specific levels.
   1. UFH. Serial measurement of activated PTT (aPTT) is most useful in evaluating the anticoagulant activity.
   2. LMWH. Specific anti-factor Xa activity is the preferred test if available, although aPTT can also be monitored.
2. Heparin-induced thrombocytopenia assays. Screening tests for HIT antibodies directed against platelet factor 4 (PF4)/heparin complexes are available at reference labs and some academic medical laboratories. This can be followed by functional tests such as a serotonin release assay (SRA) or heparin-induced platelet activation test if the HIT antibody result is indeterminate.
3. Other useful laboratory studies include electrolytes (evaluate for hyperkalemia), BUN, creatinine, and complete blood count. Thrombin time, fibrinogen, and prothrombin time (PT/INR) may be useful in consideration of other causes of bleeding.

1. Emergency and supportive measures
   1. If clinically significant bleeding occurs, be prepared to treat shock with blood transfusion and fresh-frozen plasma.
   2. Obtain immediate neurosurgical consultation if intracranial bleeding is suspected.
2. Specific drugs and antidotes
   1. Studies and case reports are conflicting as to the use of reversal agents when clinically significant bleeding has not occurred.
   2. Protamine
      1. UFH. Given heparin's short duration of action, clinically insignificant bleeding may be managed by discontinuation of heparin infusion and monitoring alone. When severe bleeding occurs, UFH is effectively reversed by protamine sulfate.
         • Protamine has a rapid onset of action and effects last up to 2 hours. Redosing may be necessary.
         • Dosage calculation is based on time of last dose of heparin and volume of heparin administered.
         • Anaphylactoid reactions resulting in hypotension occur in approximately 0.2% of patients. Protamine should be reserved for life threatening bleeding and should be used with caution in pregnant patients in whom hypotension could result in fetal harm.
      2. LMWH. Protamine can effectively neutralize the antithrombin activity of LMWH, but only partially neutralizes anti-Xa activity (20-60%). Animal studies demonstrate conflicting results of the ability of protamine to reverse LMWH-associated hemorrhage, and human cases of only partial hemorrhage control have been described. Still, protamine is recommended for patients with LMWH anticoagulation and significant hemorrhage.
         • Dosing is based on the type of LMWH administered and the number of equivalent anti-factor Xa international units. Protamine administration should ideally be within 8 hours of LMWH administration.
         • Anti-Xa activity should be measured prior to and 5-15 minutes after protamine is given.
   3. Other drugs
      1. Activated factor VII has been reported to partially reverse the anticoagulant effects of LMWHs in patients with clinically significant bleeding.
      2. Tranexamic acid has been used anecdotally in cases of LMWH overdose associated with hemorrhagic complications.
      3. Animal studies have also demonstrated success with use of adenosine triphosphate, synthetic protamine variants, heparinase, and other compounds that are not yet widely available.
3. Decontamination Not required. Oral bioavailability of UFH and LMWH is low, and gastrointestinal decontamination is not indicated.
4. Enhanced elimination. Heparin has a small volume of distribution and exchange transfusion has been used in neonates. However, due to its short duration of action and the availability of a rapidly effective reversal agent (protamine) in cases of significant bleeding, neither exchange transfusion nor hemodialysis is generally used in heparin toxicity.