Medico

DRUG THERAPY

Drug Therapy
A L A S T A I R J . J . W O O D , M . D. , Editor

H EMOSTATIC D RUGS
PIER MANNUCCIO MANNUCCI, M.D.

HEN bleeding is the consequence of a specific defect of hemostasis, the goal of treatment is to correct the defect. A typical example is the replacement of factor VIII by transfusion in patients with hemophilia. Specific treatment may be impossible, however,because bleeding may result from multiple defects or because no cause can be identified. In such situations, nontransfusional drugs that help to stop bleeding are indicated.1 These drugs may also be indicated for patients who refuse blood transfusion or for those who undergo surgical procedures associated with large blood losses necessitating many transfusions of donated blood. Many nontransfusionalhemostatic drugs have been evaluated, but only a few have proven clinical efficacy. This article will review antifibrinolytic amino acids (aminocaproic acid and tranexamic acid), aprotinin, desmopressin, and conjugated estrogens.
ANTIFIBRINOLYTIC AMINO ACIDS

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40 to 50 percent, as documented in a randomized controlled trial in 76 women.8 The drug is thought to act by inhibiting plasminogenactivator, which is present in high concentrations in the endometrium.8 Its use is recommended only when the presence of organic lesions in the uterus has been ruled out and when combined estrogen–progestogen preparations, which control dysmenorrhea and menstrual irregularity more effectively, are unacceptable or contraindicated. The recommended oral dose of tranexamic acid is 10 to 15 mg perkilogram of body weight every eight hours, from the onset of menstrual bleeding until it is arrested.
Gastrointestinal Bleeding

The use of antifibrinolytic drugs in patients with gastrointestinal lesions that cause bleeding is rational, because the local concentration of fibrinolytic enzymes is high in the digestive tract.9 Clinical trials of tranexamic acid in patients with upper gastrointestinalbleeding have had conflicting results.1,6 A metaanalysis of results in 1267 patients with peptic ulcers, mucosal erosions, or other causes of bleeding found reductions of 20 to 30 percent in recurrent bleeding, 30 to 40 percent in the need for surgery, and 40 percent in mortality.10 Despite these results, tranexamic acid is not widely used to treat patients with bleeding from the upper digestivetract because of the efficacy of other medical and endoscopic treatments.
Bleeding in the Urinary Tract

Two synthetic derivatives of the amino acid lysine, 6-aminohexanoic acid (aminocaproic acid) and 4-(aminomethyl)cyclohexanecarboxylic acid (tranexamic acid), have antifibrinolytic activity in humans.2,3 Both drugs bind reversibly to plasminogen and thereby block the binding of plasminogen tofibrin and its activation and transformation to plasmin (Fig. 1).4,5 Aminocaproic acid and tranexamic acid (which is about 10 times more potent than aminocaproic acid and has a longer half-life) are effective even when bleeding is not associated with laboratory signs of excessive fibrinolysis.6 Since both drugs enter the extravascular space and accumulate in tissues,7 the basis for their efficacyis thought to be the inhibition of tissue fibrinolysis and the consequent stabilization of clots.
Primary Menorrhagia

Excessive menstrual bleeding is the most frequent cause of iron-deficiency anemia in women of reproductive age. Tranexamic acid reduces blood loss by

The urine and the urinary tract mucosa are very rich in plasminogen activators, which facilitate the lysis of clots.7 Afterprostatectomy, urine dissolves clots in the prostatic cavity, resulting in hematuria and sometimes anemia. In clinical trials involving patients who had undergone prostatectomy, aminocaproic acid or tranexamic acid reduced blood loss by approximately 50 percent, as compared with placebo.11-13 The recommended dosage of tranexamic acid is 10 to 15 mg per kilogram every eight hours intravenously,...