Review Question - QID 213069

Unfractionated heparin works in the coagulation cascade by promoting the ability of antithrombin III to inhibit factors IIa, III, Xa.

Heparin works by binding to and enhancing the ability of antithrombin III to inhibit factors IIa, III, Xa. It is metabolized by the liver. The risks associated with the use of unfractionated heparin include bleeding and heparin induced thrombocytopenia (HIT). The reversal agent is protamine sulfate.

Agnelli et al. reviewed direct thrombin inhibitors for the prevention of VTE after major orthopaedic surgery. They reported widespread use, however, limitations in the use of unfractionated heparin and low-molecular-weight heparins. They highlighted that direct thrombin inhibitors (Ximelagatran) inactivate thrombin without requiring any plasma cofactor, inhibit both free and fibrin-bound thrombin, and do not appreciably bind to plasma proteins. They concluded that the features of rapid absorption, conversion, bioavailability, low variability, dose-time, food independency, and the predictable anticoagulant activity make direct thrombin inhibitors an attractive antithrombotic agent especially for prolonged out-of hospital prophylaxis.

Kwong et al. reviewed the efficacy and safety of fondaparinux, a selective factor Xa inhibitor and reported its efficacy and safety in 4 phase III clinical trials. They reported fondaparinux usage resulted in an overall 55% decrease in the risk of venous thromboembolism (VTE) relative to the low-molecular-weight heparin enoxaparin without increasing the incidence of clinically relevant bleeding, which was similarly low for both agents. They concluded that the superior efficacy of fondaparinux relative to enoxaparin is the result of its unique mechanism of action, clinical pharmacology.

McLynn et al. investigated the risk factors and chemoprophylaxis for VTE in elective spine surgery. They reported that independent risk factors for VTE included greater age, male gender, increasing body mass index, dependent functional status, lumbar spine surgery, longer operative time, perioperative blood transfusion, longer length of stay, and other postoperative complications. The majority of patients received unfractioned heparin and they observed this did not significantly influence the rate of VTE, but was associated with a significant increase in hematoma requiring a return to the operating room. They concluded that there is insufficient evidence to support the routine use of chemoprophylaxis in low-risk patients, and recommended full consideration of risks and benefits after elective spine surgery.

Figure A depicts the coagulation cascade, with the factor circled in red (IIa) being the target of unfractionated heparin, through its effect on antithrombin III.

Incorrect Answers:
Answer 1: Aspirin irreversibly blocks the formation of thromboxane A2 in platelets, which inhibits platelet aggregation and thus the formation of a clot.
Answer 2: Fondaparinux is an indirect factor Xa inhibitor that works through antithrombin III. Unlike unfractionated heparin, it is selective for factor X and does not have effect on factor IIa.
Answer 3: Rivaroxaban has a direct effect on factor Xa inhibition, not factor IIa.
Answer 4: TXA competitively inhibits the activation of plasminogen.