Page 2448 - Hematology_ Basic Principles and Practice ( PDFDrive )

2186 Part XII Hemostasis and Thrombosis

Alteplase
F EGF K1 K2 P

K H R R
296
299
A A A A

Tenecteplase
F EGF K1 K2 P

Desmoteplase
F EGF K1 P

Reteplase
K2 P
Fig. 149.11 DOMAIN STRUCTURES OF ALTEPLASE (TISSUE-TYPE PLASMINOGEN ACTIVA-
TOR [t-PA]), TENECTEPLASE, DESMOTEPLASE, AND RETEPLASE. The finger (F), epidermal growth
factor (EGF), first and second kringles (K1 and K2, respectively), and protease (P) domains are illustrated.
The glycosylation site (Y) on K1 has been repositioned in tenecteplase to endow it with a longer half-life. In
addition, a tetra-alanine substitution in the protease domain renders tenecteplase resistant to type 1 plasmino-
gen activator inhibitor inhibition. Desmoteplase differs from alteplase and teneteplase in that it lacks a K2
domain. Reteplase is a truncated variant that lacks the F, EGF, and K1 domains.

major soluble degradation product of cross-linked fibrin, binds Tenecteplase
alteplase and plasminogen with high affinity. Consequently, (DD)E
is as potent as fibrin as a stimulator of plasminogen activation by A genetically engineered variant of t-PA, tenecteplase was designed
alteplase. Whereas plasmin generated on the fibrin surface results in to have a longer half-life than t-PA and to be resistant to inactivation
thrombolysis, plasmin generated on the surface of circulating (DD) by PAI-1. To prolong its half-life, a new glycosylation site was added
E degrades fibrinogen. Fibrinogenolysis results in the accumulation to the first kringle domain (see Fig. 149.11). Because addition of this
of fragment X, a high-molecular-weight clottable fibrinogen degrada- extra carbohydrate side chain reduced fibrin affinity, the existing
tion product. Incorporation of fragment X into hemostatic plugs glycosylation site on the first kringle domain was removed. To render
formed at sites of vascular injury renders them susceptible to lysis. the molecule resistant to inhibition by PAI-1, a tetra-alanine substitu-
This phenomenon may contribute to alteplase-induced bleeding. tion was introduced at residues 296 to 299 in the protease domain,
A trial comparing alteplase with streptokinase for treatment of the region responsible for the interaction of t-PA with PAI-1.
patients with acute myocardial infarction demonstrated significantly Tenecteplase is more fibrin specific than t-PA. Although both
lower mortality with alteplase than with streptokinase, although the agents bind to fibrin with similar affinity, the affinity of tenecteplase
absolute difference was small. The greatest benefit was seen in patients for (DD)E is significantly lower than that of t-PA. Consequently,
less than 75 years of age with anterior myocardial infarction who (DD)E does not stimulate systemic plasminogen activation by
presented less than 6 hours after symptom onset. tenecteplase to the same extent as t-PA. As a result, tenecteplase
For treatment of acute myocardial infarction or acute ischemic produces less fibrinogenolysis than t-PA.
stroke, alteplase is given as an intravenous infusion over 60 to 90 For coronary fibrinolysis, tenecteplase is given as a single intrave-
minutes. The total dose of alteplase usually ranges from 90 to 100 mg. nous bolus. In a large phase III trial in which almost 17,000 patients
Allergic reactions and hypotension are rare, and alteplase is not were enrolled, the 30-day mortality rate with single-bolus tenecteplase
immunogenic. was similar to that with accelerated dose t-PA. 40,41 Although rates of