Page 2446 - Hematology_ Basic Principles and Practice ( PDFDrive )

2184 Part XII Hemostasis and Thrombosis

When compared with warfarin in patients with atrial fibrillation, the Plasminogen
higher-dose edoxaban regimen (60 mg once daily with dose reduc- activators
tion to 30 mg once daily for the indications listed earlier) was non-
inferior for prevention of stroke and systemic embolism, but it was Plasmin activator
38
associated with less intracranial bleeding and less major bleeding. inhibitors
In patients with venous thromboembolism who had received at least Plasminogen Plasmin
5 days of heparin, edoxaban was noninferior to warfarin for preven-
tion of recurrent venous thromboembolism and was associated with α -Antiplasmin
2
less bleeding. 39
Fibrin Fibrin degradation
products
Dosing
Fig. 149.8 FIBRINOLYTIC SYSTEM AND ITS REGULATION. Plas-
Edoxaban is given once daily at a dose of 60 mg, both for treatment minogen activators convert plasminogen to plasmin. Plasmin then degrades
of venous thromboembolism and for stroke prevention, in patients fibrin into soluble fibrin degradation products. The system is regulated at two
with atrial fibrillation. The dose is reduced to 30 mg once daily in levels. Type 1 plasminogen activator inhibitor (PAI-1) regulates the plasmino-
patients who have a body weight of 60 kg or less, have a creatinine gen activators, whereas α 2 -antiplasmin serves as the major inhibitor of
clearance of 15 to 50 mL/min, or are taking potent P-GP inhibitors plasmin.
such as verapamil, quinidine, or dronedarone. In the United States,
there is a black box warning against the use of edoxaban in patients
with atrial fibrillation who have a creatinine clearance over 95 mL/ Mechanism of Action
min.
Commonly used fibrinolytic agents include streptokinase, recombi-
nant tissue-type plasminogen activator (rt-PA), which is also known
Monitoring as alteplase or activase, and two recombinant derivatives of rt-PA,
tenecteplase and reteplase. All of these agents act by converting the
Edoxaban prolongs the prothrombin time more than the aPTT, but proenzyme, plasminogen, to plasmin, the active enzyme (Fig. 149.8).
its effects on the prothrombin time are reagent dependent. Plasma Plasmin then degrades the fibrin matrix of thrombi, thereby produc-
edoxaban concentrations can be quantified using an anti–factor Xa ing soluble fibrin degradation products.
assay with edoxaban calibrators. Endogenous fibrinolysis is regulated at two levels. Plasminogen
activator inhibitors, particularly the type 1 form, known as PAI-1,
prevent excessive plasminogen activation by regulating the activity of
Drug Interactions tissue-type plasminogen activator (t-PA) and urokinase-type plas-
minogen activator (u-PA). Once plasmin is generated, plasmin
Edoxaban is a substrate of P-GP, and coadministration with potent inhibitors, particularly α 2 -antiplasmin, regulate it. The plasma con-
P-GP inhibitors such as quinidine, verapamil, or dronedarone centration of plasminogen is twofold higher than that of α 2 -
increases drug exposure and has the potential to increase the risk of antiplasmin. Consequently, with pharmacologic doses of plasminogen
bleeding. activators, the concentration of plasmin that is generated can exceed
that of α 2 -antiplasmin. In addition to degrading fibrin, unregulated
plasmin also can degrade fibrinogen and other clotting factors. This
Side Effects process, which is known as the systemic lytic state, reduces
the hemostatic potential of the blood and increases the risk of
The major side effect is bleeding. Management of bleeding with bleeding.
edoxaban is identical to that with rivaroxaban and apixaban. Edoxa- The endogenous fibrinolytic system is geared to localize plasmin
ban crosses the placenta and should not be used in pregnant women. generation to the fibrin surface. Both plasminogen and t-PA bind to
The safety of edoxaban in women who are breastfeeding and in fibrin to form a ternary complex that promotes efficient plasminogen
children has not been established. activation. In contrast to free plasmin, plasmin generated on the
fibrin surface is relatively protected from inactivation by α 2 -
antiplasmin, a feature that promotes fibrin dissolution. Furthermore,
FIBRINOLYTIC DRUGS C-terminal lysine residues exposed as plasmin degrades fibrin serve
as binding sites for additional plasminogen and t-PA molecules. This
Role of Fibrinolytic Therapy creates a positive feedback that enhances plasmin generation. When
used pharmacologically, the various plasminogen activators capitalize
Used to degrade thrombi, fibrinolytic drugs can be administered on these mechanisms to a lesser or greater extent.
systemically or they can be delivered via catheters directly into the There are two pools of plasminogen: circulating plasminogen and
substance of the thrombus. Systemic delivery is used for treatment of fibrin-bound plasminogen (Fig. 149.9). Plasminogen activators that
acute myocardial infarction, acute ischemic stroke, and most cases of preferentially activate fibrin-bound plasminogen are considered fibrin
massive pulmonary embolism. The goal of therapy is to produce rapid specific. In contrast, nonspecific plasminogen activators do not dis-
thrombus dissolution, thereby restoring antegrade blood flow. In the criminate between fibrin-bound and circulating plasminogen. Activa-
coronary circulation, restoration of blood flow reduces morbidity and tion of circulating plasminogen results in the generation of unopposed
mortality by limiting myocardial damage, whereas in the cerebral plasmin that can trigger the systemic lytic state. Alteplase and its
circulation, rapid thrombus dissolution decreases the neuronal death derivatives are fibrin-specific plasminogen activators, whereas strep-
and brain infarction that produce irreversible brain injury. For tokinase is a nonspecific agent.
patients with massive pulmonary embolism, the goal of fibrinolytic
therapy is to restore pulmonary artery perfusion.
Peripheral arterial thrombi and thrombi in the proximal deep Streptokinase
veins of the leg are most often treated using a catheter-directed
approach. Catheters with multiple side holes can be used to deliver Unlike other plasminogen activators, streptokinase is not an enzyme
fibrinolytic drugs. In some cases, intravascular devices that fragment and does not directly convert plasminogen to plasmin. Instead,
and extract the thrombus are used to hasten treatment. streptokinase forms a 1 : 1 stoichiometric complex with plasminogen.