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402 Part V: Therapeutic Principles Chapter 25: Antithrombotic Therapy 403

administered in therapeutic doses, streptokinase is an effective throm- modifications in reteplase include removal of the finger, kringle 1, and
bolytic agent. The streptokinase–plasmin(ogen) complex can bind EGF (epidermal growth factor) receptor domains. These changes result
to fibrin through the “kringle” domains of plasmin and activate clot- in enhanced fibrin specificity and a significantly longer half-life of 15
bound plasminogen to accelerate clot lysis (Chap. 135), but can also act minutes compared to 4 minutes with t-PA, so it can be administered
on plasminogen in the blood to produce plasmin, giving rise to systemic as an intravenous bolus rather than a continuous infusion. Its mode
proteolysis termed the lytic state. This results in consumption of plas- of administration (two 10-U IV boluses given over 2 minutes, 30 min-
minogen and α -antiplasmin, degradation of fibrinogen, factor V, and utes apart) make it particularly useful for prehospital administration in
2
factor VIII, proteolysis of platelet membrane proteins by plasmin, and remote areas, or areas with limited access to primary percutaneous cor-
platelet activation. Streptokinase has a rapid plasma clearance with a onary interventions. 129
half-life of approximately 20 minutes, but the duration of the proteolytic
effect is more prolonged. 104 TENECTEPLASE
Streptokinase can be used to treat either venous or arterial throm-
bosis. Higher doses given over a shorter time are typically used for Tenecteplase (TNK) is another bioengineered variant of t-PA with a lon-
arterial disease. For either venous or arterial thrombosis, a sufficient ger half-life, increased resistance to inactivation by plasminogen activa-
dose must be administered to overcome circulating neutralizing anti- tor inhibitor-1, and improved fibrin specificity. Advantages include a
bodies, which are common because of the frequency of streptococcal longer half-life, greater fibrin specificity, ease and rapidity of adminis-
infections in the population. Occasionally, individuals have a high titer tration, and similar clinical efficacy as t-PA for treatment of acute myo-
of antibodies that neutralize this amount of streptokinase, resulting in cardial infarction. It has a half-life of more than 30 minutes and can
resistance. Streptokinase is antigenic, and high-titer antibodies develop be administered as a single IV bolus. Large studies in patients with ST
1 to 2 weeks after use, precluding retreatment until the titer declines. elevation myocardial infarction have shown it to be equivalently effec-
104
High titers can also cause febrile or hypotensive reactions. The first tive as other t-PA derivatives. The PEITHO study examined the use of
large study to demonstrate the utility of coronary reperfusion employed heparin with TNK or placebo in hemodynamically stable patients with
streptokinase. Although not widely used in North America, streptok- large pulmonary emboli associated with right ventricular dysfunction.
105
inase is still extensively used given its low cost, widespread availability, Thrombolysis resulted in a reduction in the primary end point of death
and familiarity. or hemodynamic decompensation at 7 days following randomization
(6 percent vs. 3 percent). The administration of thrombolytic agents
TISSUE-TYPE PLASMINOGEN ACTIVATOR was associated with increased bleeding complications, which was more
prominent in elderly patients.
AND RECOMBINANT TISSUE PLASMINOGEN
ACTIVATOR (ALTEPLASE)
Tissue-type plasminogen activator (t-PA) is a naturally occurring plas- ANTIPLATELET DRUGS
minogen activator that is structurally and immunologically distinct Platelets play an important role in hemostasis and thrombosis and
from urokinase. t-PA is synthesized by endothelial cells as a single-chain inhibitors of platelet function are important therapeutic agents (Chap.
polypeptide and was originally produced from cell culture for phar- 134). Platelets adhere to exposed subendothelium, become activated,
macologic use, but is now synthesized by recombinant techniques release contents of their dense and α granules, and form aggregates.
(alteplase). t-PA directly converts plasminogen to plasmin in a reaction Additional platelets from the circulating blood are then recruited by
that is accelerated several-hundred-fold in the presence of fibrin. In the adenosine diphosphate (ADP), which is released from dense granules,
absence of fibrin, t-PA has much less activity, and this property accounts and also by thromboxane A synthesized by activated platelets in the
2
for the relative “fibrin specificity” of t-PA observed physiologically. aggregate. Simultaneous with the initial platelet adhesion and aggrega-
However, when administered pharmacologically in a high dose, signifi- tion, thrombin generation is initiated. The activated platelet phospho-
cant proteolysis of plasma fibrinogen often occurs, but this is typically lipid membrane is an effective surface for binding of coagulation factors
less prominent than observed with treatment using either streptokinase to enhance the rate of thrombin generation. As thrombin is formed
or urokinase. The half-life of t-PA following intravenous administra- it activates additional platelets and also cleaves fibrinopeptides from
tion is approximately 5 minutes, which requires a constant infusion to fibrinogen to form fibrin in and around the platelet plug, consolidating
maintain therapeutic plasma levels. t-PA is not antigenic because it is a it. The role of platelets in initiating thrombosis is greater in the arterial
physiologic enzyme. 104 circulation than in the venous circulation because higher shear forces
t-PA has been evaluated in treatment of VTE, myocardial infarc- present in arteries activate platelets. Consequently, antiplatelet drugs are
tion, stroke, catheter thrombosis, and peripheral arterial occlusion. In more effective in arterial than in venous thrombosis. Table 25–6 sum-
patients with PE, a regimen of 100 mg intravenously over 2 hours results marizes the types of drug, their use in clinical settings, their mechanism
in a high rate of clot lysis and hemodynamic improvement. t-PA has of action, and their dosages.
been evaluated in many large studies for acute myocardial infarction
and administration results in improved mortality and morbidity. t-PA
has also been evaluated in treatment of stroke and results in significant CYCLOOXYGENASE-1 INHIBITORS
benefit in highly selected patients who are treated within hours of symp- Cyclooxygenase (COX)-1 is an enzyme that is present in most cells. It
tom onset (Chap. 135). In the CaVenT study, use of alteplase in cathe- converts arachidonic acid released from membrane phospholipids by
106
ter-directed thrombolysis of ileofemoral DVT resulted in an 18 percent phospholipase A or phospholipase C and diacylglycerol to prostaglan-
2
reduction in postthrombotic syndrome. din (PG) G (Chap. 112). A peroxidase converts PGG to PGH , which
2
2
2
is then converted by thromboxane synthase in platelets to thrombox-
ane A . Thromboxane A is a potent activator of platelets. In endothelial
RETEPLASE cells, PGH is converted to prostacyclin, a potent inhibitor of platelet
2
2
2
Recombinant technology has been used to engineer many t-PA mutants function, through an increase in intraplatelet cyclic adenosine mono-
in an attempt to improve pharmacologic properties. The structural phosphate (cAMP).

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