Heparin

Medications

• Unfractionated Heparin (Heparin)
• Low Molecular Weight Heparin (LMWH): Dalteparin, Enoxaparin, Tinzaparin

Indication

Used for prevention and treatment of venous thromboembolic events; non-ST elevation acute coronary syndrome (heparin, enoxaparin); prevention of embolism associated with atrial fibrillation and prosthetic heart valves; as an anticoagulant for extracorporeal circuits in dialysis procedures and during vascular and cardiac surgery; and treatment of peripheral arterial embolism (heparin).

Mechanism:

• Unfractionated heparin is an indirect anticoagulant, requiring a cofactor (antithrombin or antithrombin III) to express its activity. Unfractionated heparin alters the stereochemistry of antithrombin (AT) thereby catalyzing the subsequent inactivation of thrombin (factor IIa) and factor Xa; and to a lesser extent IXa, XIa and XIIa.
• Inhibition of thrombin requires simultaneous binding of heparin to both AT (via a unique pentasaccharide sequence) and to thrombin. In contrast, inhibition of factor Xa requires binding of the drug to anti-thrombin III (via its pentasaccharide) without additional requirement for binding to Xa. Heparin is heterogenous with respect to its molecular weight and not all of the molecules are long enough to bind to both AT and thrombin. It also binds to other cells making its activity less predictable and anticoagulant response variable. Only one third of heparin molecules contain the high-affinity pentasaccharide required for anticoagulant activity.
• Low molecular weight heparins (LMWHs) are derived from heparin (fragments of heparin). LMWH has a reduced ability to (bind AT and thrombin) inactivate thrombin. Activity of LMWH is largely mediated by anti-factor Xa activity (ratio of anti-factor Xa to antithrombin activity is between 4:1 and 2:1 for low molecular weight heparins compared to 1:1 for for unfractionated heparin).

Pharmacology

Unfractionated heparin:

• Unfractionated heparin's onset of action is almost immediate following direct IV injection, with a peak onset of action between 3-10 minutes. Unfractionated heparin administered subcutaneously is poorly and variably bioavailable and has an onset of action within 20-60 minutes, with peak levels at 2-4 hours. The bioavailability of subcutaneously administered heparin is dose-dependent and the drug may continue to be absorbed over 8-16 hours.
• The half-life of heparin when given as an IV infusion is 60-90 minutes in healthy adults. However, the half-life of heparin increases with increasing heparin doses. The half-life is approximately 60 min with an IV bolus of 100 units/kg, 90 minutes with a bolus of 200 units/kg or 150 min with a bolus of 400 units/kg. The half-life is also prolonged in hepatic impairment and cirrhosis, and may be slightly prolonged in severe renal impairment. While such data is unavailable specifically for subcutaneous unfractionated heparin, the effective duration of action is likely to be predominantly determined by its lengthy absorption phase.

Low molecular weight heparins:

• Dalteparin is dosed q24h or q12h subcutaneously for therapeutic dosing, once daily for prophylactic dosing. Enoxaparin is generally dosed q12h subcutaneously but may also be administered as a once daily dose for prophylaxis. Tinzaparin is always dosed q24h subcutaneously for both therapeutic and prophylactic dosing. Peak levels after subcutaneous administration are generally observed approximately 4 hours post subcutaneous injection.
• When compared to heparin, the bioavailability of LMWH administered subcutaneously is higher (~90%), less variable, and not dose-dependent.
• The half-lives of LMWH administered subcutaneously vary between 3 -- 4.5 hours. Half-life of LMWH is prolonged in renal impairment.

Laboratory Monitoring

• Unfractionated heparin: aPTT with therapeutic range established by the local laboratory. In general, the aPTT ratio should be 2.0-3.0 times control.
• Low molecular weight heparins: Laboratory monitoring is not usually necessary, but may be required in patients at extremes of body weight (less than 45 kg or greater than 120 kg), pregnant patients or in those with renal impairment. In this case, measuring anti-Xa levels should be considered, in consultation with a specialist.

Reversal

Protamine

• Protamine is a protein derived from salmon (or related fish) sperm that complexes with heparin to form an inactive stable salt -- this will rapidly reverse heparin's anticoagulant effects. In contrast to heparin, protamine does not bind to ultralow molecular weight fragments in low molecular weight heparins, such that protamine will entirely neutralize the anti-factor IIa activity but will incompletely neutralize the anti-factor Xa activity of LMWH.
• When administered alone, protamine itself has week anticoagulant properties, through inhibition of platelet aggregation and interaction with coagulation proteins. Protamine also reduces systolic and diastolic blood pressure and decreases heart rate and systemic vascular resistance. Risk of hypotension or bradycardia is minimized by administering the drug slowly.
• Use of protamine should take into consideration the pharmacokinetics of both protamine and the heparin or LMWH being reversed. Protamine has a rapid onset of action and neutralization of heparin occurs within 5 minutes. Because excessive protamine can act as an anticoagulant, the dose chosen should be an underestimation of that which is needed.
• Protamine is indicated for neutralization of heparin or low molecular weight-heparin heparins in severe overdosage. Protamine should be administered in patients with a prolonged aPTT (especially if greater than 3 times control) plus persistent or moderately severe bleeding.
• Protamine is contraindicated in patients with a history of hypersensitivity to the medication. Risk of hypersensitivity reaction (including anaphylaxis) is increased in patients with known sensitivity to fish, vasectomized or infertile patients and patients who have received protamine-containing insulin, due to preformed antibodies against protamine sulphate. If heparin overdose or suspected overdose:
• For initial evaluation, the following tests have been recommended: ACT, thrombin time, heparin-neutralization thrombin time, heparin activity, CBC and platelets, prothrombin time and partial thromboplastin time
• Either aPTT or ACT should be used to monitor the effect of protamine
• Coagulation tests are performed 5-15 minutes after protamine administration
• In the case of cardiopulmonary bypass, heparin rebound has been reported (likely due to a prolonged half-life as a result of the higher heparin doses used in this scenario), therefore, repeat aPTT or ACT should be performed in 2-8 hours Protamine Dosing for Heparin Overdose
• In general, 1 mg protamine will neutralize 100 units (90-115 units) of heparin
• The appropriate dose should be calculated up to a 50 mg maximum
• Each vial of heparin contains its own protamine neutralization factor on the label, indicating the amount in mg of protamine required to neutralize 1,000 units of heparin

Dosing of Protamine for Reversal of Heparin

Situation Protamine Regimen

• Heparin overdose with a known dose
• Consider the half-life of heparin (60-90 minutes). If heparin was given by intravenous (IV) injection,
• Dose the protamine based on time since heparin administration.
• Time since heparin administration: Protamine dose per 100 units of heparin administered
• 0 -- 29 minutes: 1 mg
• 30 -- 59 minutes: 0.5 -- 0.75 mg
• 60 -- 119 minutes: 0.375 -- 0.5 mg
• Greater than 2 hours: 0.25 -- 0.375 mg If heparin was given as a continuous IV infusion,
• Stop the heparin infusion
• Base dose of protamine only on the heparin received by the patient in the last four hours.
• Example #1: if patient is bleeding and has been receiving a heparin infusion at 1,000 units/hr, the recommended dose of protamine would be 40 mg.
• Example #2: if a heparin infusion at 1000 units/hr was stopped one hour ago, the dose of protamine would be 15 mg (because the half-life of heparin is approximately 1 hour, and the remaining amount of heparin to be neutralized would be 50% of 3000, or 1500 units).
• Alternatively, an empiric dose of protamine 25-50 mg may be given If heparin was given by deep SUBCUT injection,
• Calculate protamine dose: 1 -- 1.5 mg protamine for each 100 units of heparin administered
• Administer a loading dose of 25-50mg protamine IV, then administer the remainder of the calculated dose by continuous IV infusion over 8-16 hours or the expected duration of absorption of heparin

Life-threatening bleeding secondary to excessive heparin

• Administer very slowly either diluted or undiluted over 10-20 minutes to limit rate-related hypotension

Heparin overdose with an unknown dose

If ACT available:

• ACT of 150seconds -- no protamine
• ACT 200-300s -- protamine 0.6 mg/kg
• ACT 300-400s -- protamine 1.2 mg/kg If ACT not available:
• Give 25-50mg IV and continue to monitor

Protamine Dosing for Low Molecular Heparin Overdose

• There is incomplete neutralization by protamine of the LMWHs. A maximum of about 60--75% (dalteparin) or 60% (enoxaparin) or 60% (tinzaparin) of the anti-factor Xa activity is neutralized with protamine sulphate.
• Dose the protamine based on time since LMWH administration
• Administer 1 mg protamine per 100 anti-factor Xa units, where 1 mg enoxaparin equals 100 anti-factor Xa units if administered within 8 hours of the LMWH. A second dose should be administered if bleeding continues
• If greater than 8 hours have elapsed since the last dose of LMWH, then a smaller dose of protamine can be administered (e.g. 0.5 mg/kg)
• If activated partial thromboplastin time (aPTT) measured 2-4h after first protamine sulphate infusion remains prolonged, or if bleeding continues, a second dose of 0.5 mg protamine sulphate may be given per 100 anti-factor Xa units of LMWH administered.
• Time since LMWH administration: Protamine dose
• 0 -- 8 hours: 1 mg per 100 anti-factor Xa units of LMWH administered*
• greater than 8 hours: 0.5 mg per 100 anti-factor Xa units of LMWH administered*

• 1 mg enoxaparin = 100 anti-factor Xa units

• If enoxaparin was administered greater than 12 hours earlier, protamine may not be required Administration instructions: (see IV manual)
• Direct IV -- maximum rate 5 mg/min or less
• Intermittent infusion (minibag) - Protamine sulphate injection may be diluted in 50 mL of sodium chloride 0.9%, dextrose 5%, resulting in an approximately 1mg/mL protamine solution. Infuse at rate of 5 mg/min or less
• Continuous IV infusion: Not usually recommended. Continuous IV infusion is only indicated for patients receiving slow continuous hemodialysis. Protamine is typically diluted as 50 mg in 100 mL sodium chloride 0.9% resulting in a 0.5 mg/mL solution. For reversal of subcutaneously administered heparin, a continuous infusion may also be required (see dose below).
• Ensure resuscitation equipment is readily available and keep patient in supine position during administration. If symptoms occur (hypotension, bradycardia, transient flushing, feeling of warmth), the infusion should be temporarily stopped until symptoms resolve, then restart at a lower rate.