Aptamer ARC19499 mediates a procoagulant hemostatic effect by inhibiting tissue factor pathway inhibitor

Waters, Emily K.; Genga, Ryan M.; Schwartz, M. C.; Nelson, Jennifer; Schaub, Robert G.; Olson, Karen A.; Kurz, Jeffrey C.; McGinness, Kathleen E.

doi:10.1182/blood-2010-10-311936

Cited by 129 publications

(122 citation statements)

References 44 publications

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“…More recently, two different kinds of TFPI inhibitors have been investigated: sulfated polysaccharides 16,19 and aptamers. 17,18 Our study, using a strategy to inhibit TFPI that differs from the three previously published methods, confirms the potential interest of this target with regards to restoring blood clotting in hemophilia patients with or without inhibitors.…”

Section: Discussionsupporting

confidence: 73%

“…15 In addition, other approaches to neutralizing TFPI have been shown to be active ex vivo and in animal models. [16][17][18][19] Here, we propose a new approach to unlock the tenase complex of hemophilia patients with or without inhibitor. In contrast to activated factor X (FXa), Gla-domainless FXa (GDXa) is unable to bind to procoagulant phospholipids and is almost completely devoid of procoagulant activity.…”

Section: Introductionmentioning

confidence: 99%

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Gla-domainless factor Xa: molecular bait to bypass a blocked tenase complex

Marlu¹,

Polack²

2012

Haematologica

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Gla-domainless factor Xa: molecular bait to bypass a blocked tenase complex

Marlu¹,

Polack²

2012

Haematologica

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“…The selective production of TFPIα by platelets, compared with the production of TFPIβ by other mouse tissues, suggests that platelet TFPI may have a unique function in the regulation of hemostasis and/or thrombosis. Pharmaceutical agents for treatment of hemophilia that inhibit TFPI are in development (19,20). The data presented here suggest that development of pharmaceutical agents that specifically target platelet TFPI, but not endothelial TFPI, may allow hemostasis at the site of vascular injury in patients with hemophilia while minimizing the potential risk for thrombosis that could result from total intravascular inhibition of TFPI activity.…”

Section: Discussionmentioning

confidence: 90%

“…Additional studies of human plasma clotting assays initiated with dilute TF demonstrated that anti-TFPI antibodies shorten the clotting time of hemophilia plasma more than normal plasma, suggesting that pharmacological inhibitors of TFPI may represent a novel treatment for hemophilia (5,6). Consistent with these in vitro studies, in vivo studies performed in FVIII-deficient rabbits (18), dogs (19), and monkeys (20) have demonstrated that inhibition of TFPI activity reduces injuryinduced blood loss in animal models of hemophilia.…”

mentioning

confidence: 84%

Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia

Maroney

Cooley

Ferrel

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Tissue factor pathway inhibitor (TFPI) blocks thrombin generation via the extrinsic blood coagulation pathway. Because the severe bleeding in patients with hemophilia occurs from deficiency of intrinsic blood coagulation pathway factor VIII or IX, pharmacological agents that inactivate TFPI and, therefore, restore thrombin generation via the extrinsic pathway, are being developed for treatment of hemophilia. Murine models of combined TFPI and factor VIII deficiency were used to examine the impact of TFPI deficiency on bleeding and clotting in hemophilia. In breeding studies, Factor VIII null (F8 −/− ) did not rescue the embryonic death of TFPI null (Tfpi −/− ) mice. Tfpi +/− did not alter the bleeding phenotype of F8 −/− mice. However, total inhibition of intravascular TFPI through injection of anti-TFPI antibody mitigated tail vein bleeding. Interestingly, tail blood loss progressively decreased at doses greater than needed to totally inhibit plasma TFPI, suggesting that inhibition of a sequestered pool of TFPI released at the injury site mitigates bleeding. Because TFPI is sequestered within platelets and released following their activation, the function of platelet TFPI was examined in F8 −/− mice lacking hematopoietic cell TFPI that was generated by fetal liver transplantation. Blood loss after tail transection significantly decreased in Tfpi +/− ;F8 −/− mice with hematopoietic Tfpi −/− cells compared with Tfpi +/− ;F8 −/− mice with Tfpi +/+ hematopoietic cells. Additionally, following femoral vein injury, Tfpi +/− ;F8 −/− mice with Tfpi −/− hematopoietic cells had increased fibrin deposition compared with identical-genotype mice with Tfpi +/+ hematopoietic cells. These findings implicate platelet TFPI as a primary physiological regulator of bleeding in hemophilia.hemostasis | Kunitz | coagulopathy

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“…Many new and adjunctive therapeutic options have been explored, including platelet infusion, 8 tranexamic acid, 9 ⑀-amino caproic acid, 10 molecules that block tissue factor pathway inhibitor, 11,12 and a combination of phospholipid and fXa 13 and fXIII. 14 Solulin is a recombinant soluble analog of human thrombomodulin.…”

Section: Introductionmentioning

confidence: 99%

Solulin increases clot stability in whole blood from humans and dogs with hemophilia

Foley

Petersen

Rea

et al. 2012

Blood

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Solulin is a soluble form of thrombomodulin that is resistant to proteolysis and oxidation. It has been shown to increase the clot lysis time in factor VIII (fVIII)-deficient plasma by an activated thrombinactivatable fibrinolysis inhibitor (TAFIa)-dependent mechanism. In the present study, blood was drawn from humans and dogs with hemophilia, and thromboelastography was used to measure tissue factor-initiated fibrin formation and tissueplasminogen activator-induced fibrinolysis. The kinetics of TAFI and protein C activation by the thrombin-Solulin complex were determined to describe the relative extent of anticoagulation and antifibrinolysis. In severe hemophilia A, clot stability increased by > 4-fold in the presence of Solulin while minimally affecting clot lysis time. Patients receiving fVIII/fIX prophylaxis showed a similar trend of increased clot stability in the presence of Solulin. The catalytic efficiencies of TAFI and protein C activation by the thrombinSolulin complex were determined to be 1.53 and 0.02/M/s, respectively, explaining its preference for antifibrinolysis over anticoagulation at low concentrations. Finally, hemophilic dogs given Solulin had improved clot strength in thromboelastography assays. In conclusion, the antifibrinolytic properties of Solulin are exhibited in hemophilic human (in vitro) and dog (in vivo/ex vivo) blood at low concentrations. Our findings suggest the therapeutic utility of Solulin at a range of very low doses. (Blood. 2012;119(15): 3622-3628) IntroductionPatients with hemophilia A have a bleeding diathesis that is usually predicted by their factor VIII (fVIII) activity level (fVIII:C). 1,2 The primary form of treatment for severe hemophilia A is replacement therapy, which involves administration of recombinant or plasmaderived fVIII. FVIII can be given either on demand or by prophylaxis, 3 and the amount needed can vary drastically depending on the treatment schedule and the type and severity of the bleed in the case of on-demand treatment. 4 The treatment developments to date have greatly improved both mortality and morbidity for individuals with hemophilia 5,6 ; however, current treatments are not 100% effective, are expensive, and are often considered inconvenient. Because single bleeding events can have devastating consequences, it is important to continue to strive for maximally effective treatments. The recent improvements in mortality and morbidity have only been observed in developed countries with the resources to fund treatment. It is currently estimated that 80% of the world's hemophilia population has little or no access to therapy 7 ; therefore, the development of costeffective alternate treatment strategies or effective factor-sparing regimes to treat bleeding is clearly necessary.Many new and adjunctive therapeutic options have been explored, including platelet infusion, 8 tranexamic acid, 9 ⑀-amino caproic acid, 10 molecules that block tissue factor pathway inhibitor, 11,12 and a combination of phospholipid and fXa 13 and fXIII. 14 Solulin is a recom...

show abstract

Aptamer ARC19499 mediates a procoagulant hemostatic effect by inhibiting tissue factor pathway inhibitor

Cited by 129 publications

References 44 publications

Gla-domainless factor Xa: molecular bait to bypass a blocked tenase complex

Gla-domainless factor Xa: molecular bait to bypass a blocked tenase complex

Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia

Solulin increases clot stability in whole blood from humans and dogs with hemophilia

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