Antithrombotics

Introductory material
at this American Heart Association site includes a concise description of the process of clotting in arteries, veins, cardiac chambers, and the microvasculature.

Antithrombin III (ATIII)
is a naturally occurring, slow, progressive inhibitor of thrombin and other coagulation enzymes. About one-third of administered heparin binds to ATIII, which undergoes configuration changes to become a more rapid acting inhibitor of thrombin, factor X, and several other coagulation enzymes (IX, XI & XII). Heparin molecules with more than 18 saccharides can inhibit thrombin. Smaller heparin fragments, with fewer saccharides, can catalyze the inhibition of factor Xa by ATIII. Heparin molecular weights vary from 3,000 to 30,000. The larger molecules are cleared more rapidly leaving the smaller molecules which have a lower ratio of antithrombin to anti-factor Xa activity.

Pharmacokinetics
of heparin are discussed in detail in the AHA monograph. Lower doses are rapidly cleared by a saturable set of mechanisms. Higher, intravenous, therapeutic doses are cleared more slowly. This leads to an apparent half life of 30 minutes following a dose of 25 U/kg to 60 minutes for 100 U/kg to 150 minutes for an intravenous bolus of 400 U/kg. Heparin bioavailability is much less with smaller subcutaneous dosages than larger intravenous doses. The therapeutic implication is that adequate dosages should be given early when rapid onset of therapeutic effectiveness is desired.

Therapeutic heparin blood levels
are 0.2 to 0.4 U/ml by protamine titration and 0.3 to 0.7 U/ml by anti-factor Xa chromogenic assay. Accordingly, the generally accepted therapeutic ratio of 1.5 to 2.5 (patient’s PTT divided by laboratory reference PTT) may be too high or too low for your institution. Nomograms can be developed that reflect the reagents used at a particular institution.

Evidence is presented
that heparin is useful for the prevention and/or treatment of

Venous thrombosis

Pulmonary embolism

Mural thrombus after myocardial infarction

Post thrombolytic coronary rethrombosis

Unstable angina

Acute myocardial infarction

Additive effectiveness when heparin is combined with aspirin is uncertain.
Additive effectiveness when heparin is used with streptokinase has not been demonstrated.
Heparin is recommended for patients treated with PTA.

Low molecular weight heparins
bind less avidly to heparin binding proteins than heparin. This makes them more biologically active at lower dosages and more therapeutically predictable. They can be given once daily without laboratory monitoring. Clinical trials are summarized that show low molecular weight heparin to be as effective as, if not more effective than, unfractionated heparin for a variety of clinical conditions. Low molecular weight heparin is superior for preventing venous thrombosis in patients undergoing hip replacement.

Recommendation summary
assumes that all dosages are adjusted to obtain an aPTT equivalent to a heparin level of 0.2 to 0.4 U/ml by protamine titration.

Condition	Dosage
Venous thromboembolism	5,000 unit bolus, then 32,000 units per 24 hours OR 17,500 units subcu every 12 hours.
Prevention of venous thromboembolism	5,000 units subcu every 12 hours for medical and general surgery patients. Higher risk patients (orthopedic procedures and prior history of venous thrombosis) receive low molecular weight heparin, unfractionated heparin adjusted to upper normal aPTT or less intense warfarin. (Low molecular weight heparin is superior to unfractionated heparin for hip replacement and to warfarin for knee replacement.)
Unstable angina and acute myocardial infarction	Absent thrombolytic treatment, give 325 mg ASA and heparin at therapeutic dosages (see venous thromboembolism above). If given to patients receiving thrombolytic treatment, the suggested dosage is 24,000 units per 24 hours. Heparin can be started with TPA but delayed 2 to 3 hours after streptokinase. [also see ACC/AHA AMI Guidelines - Ed.]

Non-hemorrhagic complications
of heparin administration include thrombocytopenia (with and without thrombosis), osteoporosis, skin necrosis, alopecia and hypoaldosteronism.

Heparin-associated thrombocytopenia
is more common with bovine than with porcine-derived product. Thrombocytopenia usually begins between 3 and 5 days, or earlier in previously exposed patients. The heparinoid, Orgaran, has been used to manage a few patients with a history of heparin-associated thrombocytopenia.

Heparin does not cross the placenta
and can be used in dosages of 15,000 units subcu every 12 hours for pregnant women with prosthetic heart valves or venous thromboembolism.

Bleeding complications
have been related to higher dosage, effectiveness of anticoagulation, intermittent vs. continuous infusion, alcohol excess, renal failure, advanced age and concomitant aspirin administration.