Medication Summary
Traditionally, fresh frozen plasma (FFP) has been the source of clotting factors used to treat coagulation factor deficiencies for which no concentrates are available. Alpha2–plasmin inhibitor (alpha2-PI) falls into this category.
Careful screening of blood donors and viral testing of donated blood (ie, for hepatitis B virus [HBV], hepatitis C virus [hPC], HIV, and human T-cell leukemia virus [HTLV] and screening for elevated alanine aminotransferase [ALT] levels) have improved the safety of blood products. Nevertheless, risks remain for a variety of reasons, including failure to detect infections during the incubation period before the results of currently available tests become positive, as well as the possible presence of other types of infections for which screening or testing is not available or for which the presence is unknown.
Those risks spurred the development of solvent/detergent-treated plasma (SDP; Octaplas). Solvent/detergent treatment results in significant inactivation of lipid-enveloped viruses (eg, HIV, HCV, HBV). In addition, SDP delivers consistent and reproducible levels of coagulation factors. In contrast to the extreme variability in FFP, leukocytes are not present, and physiologic inhibitor levels are mostly in the reference range, with the exception of a moderate reduction in the levels of alpha2-PI (approximately 0.48 IU/mL) and protein S (approximately 0.52 IU/mL).
In addition, coagulation zymogen activation does not occur, reference values of other plasma proteins and immunoglobulins are seen, and all lots have anti-hepatitis A virus (HAV) antibody levels of greater than 0.8 IU/mL, providing passive administration of antibody that may neutralize HAV. In addition, SDP lacks the largest von Willebrand multimers and has proven efficacy in the treatment of a variety of bleeding disorders.
SDP should not be used in patients with known immunoglobulin A (IgA) deficiency. [20, 21] All SDP units must be compatible with the patient's ABO blood group. Adverse reactions include minor allergic reactions, which respond to antihistamines. Rarely, noncardiogenic pulmonary edema, citrate toxicity, hypothermia, and other metabolic problems arise if large volumes are used rapidly. In addition, positive results using the direct antiglobulin test may be induced by antibodies, and hemolysis may occur, rarely. [20]
Recognition of the importance of the lysine-binding sites in various interactions in the fibrinolytic pathway led to the synthesis of lysine analogues such as epsilon-aminocaproic acid (EACA) and tranexamic acid. These synthetic lysine analogues induce a conformational change in plasminogen when they bind to its lysine-binding site. After EACA binds to it, plasminogen takes the shape of a pronate ellipsoid. The plasminogen elongates into a long structure in which former interactions between the parts are lost.
In vivo, synthetic lysine analogues probably prevent plasminogen activation and, in large doses, also bind plasmin, thereby preventing plasmin from binding to its substrate, fibrin. The tightest binding on EACA-binding sites on plasminogen occurs on kringle 1, followed by kringles 4 and 5. Interaction with kringle 2 is weak, and kringle 3 does not interact at all. A model of the structure of kringle 4 shows that the shallow trough formed by hydrophobic amino acids is surrounded by positively and negatively charged amino acids at a distance ideal for interacting with EACA.
EACA is the most widely used antifibrinolytic drug in the United States. The minimum dose needed to inhibit either normal or excessive fibrinolysis is unknown. EACA is absorbed well orally, and 50% is excreted in the urine within 24 hours. Generally, an initial loading dose is followed by a maintenance dose to adequately inhibit fibrinolysis until excess bleeding is controlled. Then, the maintenance dose is tapered until EACA can be discontinued. Rarely, myopathy and muscle necrosis can develop. Lower doses are adequate when bleeding involves the urinary tract because drug concentrations are 75-100–fold higher in urine than in plasma.
Tranexamic acid is also excreted rapidly in the urine, with more than 90% excreted within 24 hours; however, its antifibrinolytic effect lasts longer than that of EACA. Tranexamic acid inhibits fibrinolysis at lower plasma concentrations, although its serum half-life is similar to that of EACA. Therefore, tranexamic acid can be administered less frequently and at lower doses.
The dose of EACA and tranexamic acid must be reduced in patients with kidney failure.
Aprotinin, an antifibrinolytic agent used to reduce operative blood loss in patients undergoing open heart surgery, [19] has also been shown to reduce blood loss and transfusion requirements in patients undergoing orthotopic liver transplantation and in patients undergoing elective resection of a solitary liver metastasis originating from colon cancer. It was removed from markets worldwide after Fergusson et al reported an increased risk for death with aprotinin compared with EACA or tranexamic acid in high-risk cardiac surgery, but was subsequently relicensed in Europe; however, it remains unavailable in the United States. [22, 23]
Antihemophilic Agents
Class Summary
Administer inhibitors of fibrinolysis together with FFP replacement in patients with alpha 2-plasmin inhibitor deficiency (alpha 2-PI deficiency, a2-PI deficiency) who are undergoing minor surgical procedures (eg, dental extractions, sinus surgery), so that the procedures can be accomplished on an outpatient basis with the use of a single dose of product.
Concern about the possible relationship of antihemophilic agents to acute thrombotic events remains, although a causal relationship is being questioned, because the underlying disease state determines the site and extent of thrombosis.
Fresh frozen plasma (Octaplas, FFP)
Fresh frozen plasma (FFP) is plasma from a unit of whole blood separated by centrifugation and frozen within 8 hours of collection. Each unit provides all plasma proteins and clotting factors to support adequate hemostasis to treat or prevent bleeding or to treat other protein deficiencies that cannot be replaced with protein-specific concentrates.
Aminocaproic acid (Amicar)
Hemostatic agent that diminishes bleeding by inhibiting fibrinolysis of hemostatic plug. Can be used PO/IV.
Tranexamic acid (Cyklokapron)
Fibrinolytic inhibitor that can be used with FFP replacement to inhibit fibrinolysis.
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The role of alpha2-plasmin inhibitor (alpha2-antiplasmin) in fibrinolysis.
