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Blood, 15 May 2005, Vol. 105, No. 10, pp. 3764. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gilbert, G. E. Search for Related Content PubMed Articles by Gilbert, G. E. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS Comment on Chen et al, page 3902 Connubiality, inhibition, and blood coagulation Gary E. Gilbert VA BOSTON HEALTHCARE SYSTEM; BRIGHAM AND WOMEN'S HOSPITAL; HARVARD MEDICAL SCHOOL Fusion proteins, with membrane-binding annexin V coupled to the Kunitz-type domains of anticoagulants, are more effective than corresponding native anticoagulants. The prothrombinase complex is composed of factor Va and factor Xa and is assembled on a phosphatidylserine-containing membrane. This complex produces thrombin, which clots fibrinogen and activates cells. Natural inhibitors balance procoagulant activity of the prothrombinase complex. An important class of inhibitors contains Kunitz-type domains that bind tightly to the active site of factor Xa. One physiologic inhibitor with Kunitz-type domains is tissue factor pathway inhibitor (TFPI). Although it is named for inhibition of the factor VIIa–tissue factor complex, TFPI is also an inhibitor of the prothrombinase complex. Tick saliva contains another prothrombinase inhibitor with a Kunitz-type domain called tick anticoagulant peptide (TAP). TAP enables a tick to enjoy a substantial blood meal before the host's blood clots. Prothrombin competes with TAP and TFPI at the active site of prothrombinase, limiting their anticoagulant effectiveness. Prothrombin binds to the phosphatidylserine-containing membrane on which the enzyme complex is assembled, providing a competitive edge. Thus, one approach to enhancing the inhibitory action of the Kunitz-domain inhibitors would be to engineer phosphatidylserine-binding activity into these proteins so that they can better compete with prothrombin at the membrane surface. Model of the inhibition of a membrane-associated coagulation complex by the annexin V–Kunitz type protease inhibitor (ANV-KPI) fusion protein. See the complete figure in the article beginning on page 3902.   Annexin V binds to membranes containing phosphatidylserine with affinity more than 100-fold greater than that of prothrombin. This high affinity enables annexin V to compete with procoagulant enzyme complexes for binding sites on membranes containing phosphatidylserine. Thus, annexin V has independent anticoagulant properties. Chen and colleagues engineered marriages between annexin V and the tenacious protease-binding domains of 4 Kunitz-type inhibitors (see figure). The matchmaking was fruitful, as described in this issue of Blood. All 4 fusion proteins inhibit prothrombin time and partial thromboplastin time assays more effectively than the corresponding anticoagulants. One fusion protein, TAP–annexin V, was tested in a mouse carotid artery injury model. It was more effective than uncoupled TAP and annexin V in preventing carotid thrombosis. These compelling results justify further studies to determine whether these inhibitors should eventually find their way into our clinical formulary. A number of interesting questions emerge from the encouraging results in this report. Are the fusion proteins truly better competitors for enzyme complex active sites than the native Kunitz-type inhibitors? (The authors have shown that they are more potent anticoagulants, skipping the biochemical questions of superior competition for enzyme complex active sites.) Do the fusion proteins inhibit protease-mediated cell signaling to the same extent that they inhibit blood coagulation? What is the mechanism through which TAP–annexin V prevents thrombosis of a carotid artery for 2 hours when the predicted half-life is approximately 5 minutes? In summary, the report suggests exciting possibilities for the novel anticoagulants that may lead to better antithrombotic agents and that may also lead to a better understanding of the biochemistry and cell biology that support the hemostatic and thrombotic mechanisms. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Fusion proteins comprising annexin V and Kunitz protease inhibitors are highly potent thrombogenic site-directed anticoagulants Hsiu-Hui Chen, Cristina P. Vicente, Li He, Douglas M. Tollefsen, and Tze-Chein Wun Blood 2005 105: 3902-3909. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gilbert, G. E. Search for Related Content PubMed Articles by Gilbert, G. E. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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