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2016 ; 14
(9
): 1844-54
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Thrombolysis by chemically modified coagulation factor Xa
#MMPMID27359348
Pryzdial EL
; Meixner SC
; Talbot K
; Eltringham-Smith LJ
; Baylis JR
; Lee FM
; Kastrup CJ
; Sheffield WP
J Thromb Haemost
2016[Sep]; 14
(9
): 1844-54
PMID27359348
show ga
Essentials Factor Xa (FXa) acquires cleavage-mediated tissue plasminogen
activator (tPA) cofactor activity. Recombinant (r) tPA is the predominant
thrombolytic drug, but it may cause systemic side effects. Chemically modified,
non-enzymatic FXa was produced (Xai-K), which rapidly lysed thrombi in mice.
Unlike rtPA, Xai-K had no systemic fibrinolysis activation markers, indicating
improved safety. SUMMARY: Background Enzymatic thrombolysis carries the risk of
hemorrhage and re-occlusion must be evaded by co-administration with an
anticoagulant. Toward further improving these shortcomings, we report a novel
dual-functioning molecule, Xai-K, which is both a non-enzymatic thrombolytic
agent and an anticoagulant. Xai-K is based on clotting factor Xa, whose
sequential plasmin-mediated fragments, FXa? and Xa33/13, accelerate the principal
thrombolytic agent, tissue plasminogen activator (tPA), but only when localized
to anionic phospholipid. Methods The effect of Xai-K on fibrinolysis was measured
in vitro by turbidity, thromboelastography and chromogenic assays, and measured
in a murine model of occlusive carotid thrombosis by Doppler ultrasound. The
anticoagulant properties of Xai-K were evaluated by normal plasma clotting
assays, and in murine liver laceration and tail amputation hemostatic models.
Results Xa33/13, which participates in fibrinolysis of purified fibrin, was
rapidly inhibited in plasma. Cleavage was blocked at FXa? by modifying residues
at the active site. The resultant Xai-K (1 nm) enhanced plasma clot dissolution
by ~7-fold in vitro and was dependent on tPA. Xai-K alone (2.0 ?g g(-1) body
weight) achieved therapeutic patency in mice. The minimum primary dose of the tPA
variant, Tenecteplase (TNK; 17 ?g g(-1) ), could be reduced by > 30-fold to
restore blood flow with adjunctive Xai-K (0.5 ?g g(-1) ). TNK-induced systemic
markers of fibrinolysis were not detected with Xai-K (2.0 ?g g(-1) ). Xai-K had
anticoagulant activity that was somewhat attenuated compared with a previously
reported analogue. Conclusion These results suggest that Xai-K may ameliorate the
safety profile of therapeutic thrombolysis, either as a primary or
tPA/TNK-adjunctive agent.
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