Orphan drug status is a designation given by the FDA to promote development of therapies for rare disorders (see Chapter 1).
Factor XIII is a transaminase that crosslinks fibrin within a clot, thereby stabilizing it. Congenital factor XIII deficiency is a rare bleeding disorder. Recombinant factor XIII A-subunit is FDA-approved for prevention of bleeding in patients with factor XIII deficiency.
Factor X concentrate is a plasma-derived factor X preparation that is FDA-approved for control of bleeding in patients with factor X deficiency and for perioperative management of patients with mild factor X deficiency.
Protein C concentrate is a plasma-derived protein C preparation approved for treatment of life-threatening thrombosis or purpura fulminans, a life-threatening disorder involving thrombosis in skin and systemic circulation.
Recombinant antithrombin is FDA-approved for prevention of perioperative and peripartum thromboembolic events in patients with hereditary antithrombin deficiency.
FIBRINOLYTIC INHIBITORS: AMINOCAPROIC ACID
Aminocaproic acid (EACA), which is chemically similar to the amino acid lysine, is a synthetic inhibitor of fibrinolysis. It competitively inhibits plasminogen activation (Figure 34–3). It is rapidly absorbed orally and is cleared from the body by the kidney. The usual oral dosage of EACA is 6 g four times a day. When the drug is administered intravenously, a 5-g loading dose should be infused over 30 minutes to avoid hypotension. Tranexamic acid is an analog of aminocaproic acid and has the same properties. It is administered orally with a 15-mg/kg loading dose followed by 30 mg/kg every 6 hours.
Clinical uses of EACA are as adjunctive therapy in hemophilia, as therapy for bleeding from fibrinolytic therapy, and as prophylaxis for rebleeding from intracranial aneurysms. Treatment success has also been reported in patients with postsurgical gastrointestinal bleeding and postprostatectomy bleeding and bladder hemorrhage secondary to radiationand drug-induced cystitis. Adverse effects of the drug include intravascular thrombosis from inhibition of plasminogen activator, hypotension, myopathy, abdominal discomfort, diarrhea, and nasal stuffiness. The drug should not be used in patients with disseminated intravascular coagulation or genitourinary bleeding of the upper tract, eg, kidney and ureters, because of the potential for excessive clotting.
DRUGS REMOVED FROM MARKET FOR LACK OF EFFICACY OR SAFETY: APROTININ AND ACTIVATED PROTEIN C
Aprotinin is a serine protease inhibitor (serpin) that inhibits fibrinolysis by free plasmin and may have other antihemorrhagic effects as well. It also inhibits the plasmin-streptokinase complex in patients who have received that thrombolytic agent. Aprotinin was shown to reduce bleeding—by as much as 50%—from many types of surgery, especially that involving extracorporeal circulation for open-heart procedures and liver transplantation. However, clinical trials and internal data from the manufacturer suggested that use of the drug was associated with an increased risk of renal failure, heart attack, and stroke. A prospective trial was initiated in Canada but halted early because of concerns that use of the drug was associated with increased mortality. The drug was removed from the market in 2007.