Page 637 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 34 Drugs Used in Disorders of Coagulation 623

Two products are available expressly for this purpose: Autoplex for nonapproved indications. This study found an increase in
(with factor VIII correctional activity) and FEIBA (Factor arterial, but not venous, thrombotic events, particularly among
Eight Inhibitor Bypass Activity). These products are not uni- elderly individuals.
formly successful in arresting hemorrhage, and the factor IX
inhibitor titers often rise after treatment with them. Acquired
inhibitors of coagulation factors may also be treated with ORPHAN DRUGS FOR TREATMENT OF
porcine factor VIII (for factor VIII inhibitors) and recombi- RARE HEREDITARY COAGULATION
nant activated factor VII. Recombinant activated factor VII DISORDERS
(NovoSeven) increasingly is being used to treat coagulopathy
associated with liver disease and major blood loss in trauma
and surgery. These recombinant and plasma-derived factor Orphan drug status is a designation given by the FDA to promote
concentrates are very expensive, and the indications for them development of therapies for rare disorders (see Chapter 1).
are very precise. Therefore, close consultation with a hematolo- Factor XIII is a transaminase that crosslinks fibrin within a
gist knowledgeable in this area is essential. clot, thereby stabilizing it. Congenital factor XIII deficiency is a
Cryoprecipitate is a plasma protein fraction obtainable from rare bleeding disorder. Recombinant factor XIII A-subunit is
whole blood. It is used to treat deficiencies or qualitative abnor- FDA-approved for prevention of bleeding in patients with factor
malities of fibrinogen, such as that which occurs with dissemi- XIII deficiency.
nated intravascular coagulation and liver disease. A single unit of Factor X concentrate is a plasma-derived factor X preparation
cryoprecipitate contains 300 mg of fibrinogen. that is FDA-approved for control of bleeding in patients with
Cryoprecipitate may also be used for patients with factor VIII factor X deficiency and for perioperative management of patients
deficiency and von Willebrand disease if desmopressin is not with mild factor X deficiency.
indicated and a pathogen-inactivated, recombinant, or plasma- Protein C concentrate is a plasma-derived protein C prepara-
derived product is not available. The concentration of factor VIII tion approved for treatment of life-threatening thrombosis or pur-
and von Willebrand factor in cryoprecipitate is not as great as that pura fulminans, a life-threatening disorder involving thrombosis
found in the concentrated plasma fractions. Moreover, cryopre- in skin and systemic circulation.
cipitate is not treated in any manner to decrease the risk of viral Recombinant antithrombin is FDA-approved for preven-
exposure. For infusion, the frozen cryoprecipitate unit is thawed tion of perioperative and peripartum thromboembolic events in
and dissolved in a small volume of sterile citrate-saline solution patients with hereditary antithrombin deficiency.
and pooled with other units. Rh-negative women with potential
for childbearing should receive only Rh-negative cryoprecipitate
because of possible contamination of the product with Rh-positive FIBRINOLYTIC INHIBITORS:
blood cells. AMINOCAPROIC ACID

Aminocaproic acid (EACA), which is chemically similar to the
RECOMBINANT FACTOR VIIa amino acid lysine, is a synthetic inhibitor of fibrinolysis. It com-
petitively inhibits plasminogen activation (Figure 34–3). It is
Recombinant factor VIIa is approved for treatment of inherited rapidly absorbed orally and is cleared from the body by the kidney.
or acquired hemophilia A or B with inhibitors, treatment of The usual oral dosage of EACA is 6 g four times a day. When the
bleeding associated with invasive procedures in congenital or drug is administered intravenously, a 5-g loading dose should be
acquired hemophilia, or factor VII deficiency. In the European infused over 30 minutes to avoid hypotension. Tranexamic acid
Union, the drug is also approved for treatment of Glanzmann’s is an analog of aminocaproic acid and has the same properties. It
thrombasthenia. is administered orally with a 15-mg/kg loading dose followed by
Factor VIIa initiates activation of the clotting pathway by 30 mg/kg every 6 hours.
activating factor IX and factor X in association with tissue factor Clinical uses of EACA are as adjunctive therapy in hemo-
(see Figure 34–2). The drug is given by bolus injection. For philia, as therapy for bleeding from fibrinolytic therapy, and as
hemophilia A or B with inhibitors and bleeding, the dosage is prophylaxis for rebleeding from intracranial aneurysms. Treat-
90 mg/kg every 2 hours until hemostasis is achieved, and then ment success has also been reported in patients with postsurgical
continued at 3- to 6-hour intervals until stable. For congenital gastrointestinal bleeding and postprostatectomy bleeding and
factor VII deficiency, the recommended dosage is 15–30 mg/kg bladder hemorrhage secondary to radiation- and drug-induced
every 4–6 hours until hemostasis is achieved. cystitis. Adverse effects of the drug include intravascular throm-
Factor VIIa has been widely used for off-label indications, bosis from inhibition of plasminogen activator, hypotension,
including bleeding with trauma, surgery, intracerebral hemor- myopathy, abdominal discomfort, diarrhea, and nasal stuffiness.
rhage, and warfarin toxicity. A major concern of off-label use has The drug should not be used in patients with disseminated
been the possibility that thrombotic events may be increased. intravascular coagulation or genitourinary bleeding of the upper
A recent study examined rates of thromboembolic events in tract, eg, kidney and ureters, because of the potential for exces-
35 placebo-controlled trials where factor VIIa was administered sive clotting.