What Drugs Decrease Perioperative Bleeding?

Antifibrinolytic Drugs

Antifibrinolytic drugs have been used extensively in cardiac surgery, trauma surgery, and orthopedic surgery. The two main drugs in clinical use in the United States are tranexamic acid (TXA) and ε-aminocaproic acid (EACA). They are both synthetic lysine analogs that bind reversibly to the lysine-binding site of plasminogen, which, in turn, displaces plasminogen from fibrin and prevents fibrinolysis. Both drugs are excreted renally and require dose adjustment for patients with renal insufficiency. TXA has more sustained tissue antifibrinolytic activity and is 7 to 10 times as potent as EACA.

Aprotinin is a nonspecific serine protease inhibitor derived from bovine lung. It acts at several proteases, including plasmin, kallikrein, trypsin, and factor XII ( Fig. 57.1 ). Compared with the lysine analogs, aprotinin not only inhibits fibrinolysis but also complements activation and contact activation of both coagulation and inflammation. In addition, aprotinin also preserves platelet function after cardiopulmonary bypass. There is a small risk for anaphylaxis, especially with repeated exposure. It should be noted that aprotinin artificially prolongs celite-based activated clotting time (ACT) measurements; therefore a kaolin ACT test should be used. Dosing is based on kallikrein-inhibiting units (KIU). Aprotinin was withdrawn from the US market in 2008 after Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) showed an increase in the mortality rate compared with the lysine analogs (see Fig. 57.1 ).

Desmopressin

Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is a synthetic analog of the hormone arginine vasopressin, also known as antidiuretic hormone (ADH). It is Food and Drug Administration (FDA) approved for the treatment of hemophilia A (when factor VIII activity is greater than 5%), von Willebrand disease type 1, and diabetes insipidus. It has also been used off-label to treat other forms of platelet dysfunction (e.g., uremia-induced or post cardiopulmonary bypass) because of its ability to release endogenous stores of factor VIII, von Willebrand factor (vWF), and plasminogen activator, which, in turn, enhance platelet function. The recommended dose is 0.3 mcg/kg and effects are seen within 30 minutes of intravenous (IV) administration. Contraindications include moderate to severe renal insufficiency and hyponatremia. In the perioperative setting, transient hypotension caused by decreased systemic vascular resistance is the most common side effect, although this is mitigated by slow infusion. ^,

Protamine

Protamine is a strongly basic polypeptide used in the reversal of unfractionated heparin. It binds to the highly acidic heparin molecules to form a stable salt that lacks anticoagulant properties. Protamine by itself, however, is a weak anticoagulant, with effects on factor V, platelets, and fibrinolysis. Inadequate or excess doses can result in bleeding. It is not effective for reversal of low-molecular-weight heparin. Reactions may include histamine release and anaphylactic, anaphylactoid, and pulmonary vasoconstriction. Slow administration can help prevent some of these reactions. Treatment of a protamine reaction is supportive.

Vitamin K

Warfarin works by inhibiting the vitamin K-dependent gamma-carboxylation of factors II, VII, IX, and X, as well as proteins C and S. As such, warfarin can be reversed by the administration of vitamin K, and effects are seen in 4 to 6 hours if given intravenously. Oral administration requires up to 24 hours for full effect. ^, If more urgent reversal is necessary, fresh-frozen plasma (FFP) or prothrombin complex concentrates (PCCs) should be used, supplemented by vitamin K because of the short half-life of exogenous factors. The American College of Chest Physicians recommends the addition of 5 to 10 mg IV vitamin K to be given in addition to plasma transfusion for rapid reversal. Concerns over anaphylaxis have led many to avoid IV use of vitamin K, but these reactions are quite rare, and IV administration should not be avoided if urgent reversal is needed.

Prothrombin Complex Concentrates

PCCs are the recommended means of rapidly reversing warfarin anticoagulation in the setting of life-threatening bleeding or the need for an emergent/urgent procedure. They are isolated from pooled human plasma and contain varying amounts of the vitamin K-dependent clotting factors. These clotting factor concentrates are available as the following formulations: three-factor (3F; Factors II, IX, X) and four-factor (4F; Factors II, VII, IX, X, also with Proteins C, S, and some heparin to prevent VIIa and then Xa formation). In the United States, a 4F-PCC formulation is approved by the FDA for the reversal of warfarin-associated bleeding and reversal of warfarin anticoagulation in the settings previously described (Kcentra, CSL Behring, Marburg, Germany).

Compared with FFP, the theoretical advantages of PCCs include immediate availability without thawing, small volume of administration, rapid administration, and viral inactivation. Disadvantages include the potential for thromboembolic events and cost. In addition, FFP contains more than just the specific factors found in PCCs (e.g., fibrinogen).

Recombinant Activated Factor VII

Recombinant activated factor VII (rFVIIa) is FDA approved for the treatment of bleeding in congenital factor VII deficiency and in hemophilia patients with inhibitors to factor VIII or IX. It has been used off-label in a variety of scenarios, including trauma, intracranial hemorrhage, surgery, and reversal of anticoagulation. ^, The mechanism of action is related to its ability to complex with tissue factor, allowing it to activate factors X and IX, which, in turn, complex with other factors to convert prothrombin to thrombin. It should be noted that rFVIIa is a relatively expensive drug, costing approximately $10,000 for a typical adult dose ( Table 57.2 ).