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研究生:曾昱綸
研究生(外文):Yu-Lun Tseng
論文名稱:抗血栓蛇毒蛋白對嗜中性白血球附著、嗜中性白血球-血小板交互作用與其作用機轉之研究
論文名稱(外文):Action Mechanism of Anti-thrombotic Snake Venom Proteins on Neutrophil Adhesion andNeutrophil-platelet Interactions
指導教授:黃德富
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:英文
論文頁數:94
中文關鍵詞:血栓蛇毒蛋白嗜中性白血球血小板
外文關鍵詞:triflampdisintegrinsneutrophilsplateletsPSGL-1GPIbsanke venom metalloproteinases
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Disintegrins是一群具有特定胺基酸序列Arg(或Lys)-Gly-Asp之蛇毒蛋白的總稱。它們能藉由拮抗ΖIbβ3 integrin,進而抑制血小板的凝集作用。Rhodostomin是一種由馬來亞腹蛇(Calloselasma rhodostoma)純化出的disintegrin,我們首先利用它去研究disintegrin對嗜中性白血球弁鄋獐v響。將rhodostomin接合上FITC以作為探針工具,並利用流式細胞儀分析全血樣本,我們發現rhodostomin除了作用在血小板上之外,它也能作用於嗜中性白血球與單核球上。然而,rhodostomin並不作用於淋巴球上。Rhodostomin與嗜中性白血球的結合具有呈濃度相關的性質併呈現飽和的趨勢。在活化劑PMA或fMLP的存在下,rhodostomin與嗜中性白血球之結合會明顯增加。我們也證實rhodostomin不會被嗜中性白血球所吞噬,這說明了rhodostomin與嗜中性白血球的結合應具有特異性。EDTA並無法抑制rhodostomin與嗜中性白血球的結合。CD11b/CD18 (Mac-1)的天然結合物─纖維蛋白原,其能抑制rhodostomin與被PMA活化之嗜中性白血球的結合;GRGDS亦能抑制這種結合。然而,包括單株抗體7E3在內,對抗Κ與β2 integrin的抗體卻無法抑制上述的結合,暗示rhodostomin能與嗜中性白血球上其他的受體結合。Rhodostomin能部分抑制經由Mac-1受體附著於固定相纖維蛋白原上的嗜中性白血球,進而減少超氧化物的產生。我們認為超氧化物產量的減少乃歸因於附著之嗜中性白血球減少之故。上述的發現或陳酮郢hodostomin是否具抗發炎的性質提出部分的佐證。
除了disintegrins以外,腹蛇科蛇毒中已有多種具生物活性的成分被研究,這些成分能專一性的影響細胞與細胞外間質的作用。根據抗附著(anti-adhesive)的理論,某些蛇毒成分已成戊Q用來發展成抗血栓或抗血管新生藥物。利用血小板凝集器與流式細胞儀,我們首先篩選出日本龜殼花(Trimeresurus flavoviridis)蛇毒中能抑制稀釋之全血樣本中嗜中性白血球與血小板間彼此附著的成分。該蛋白成分之分子量約為28 kDa,其蛋白質N端序列類似其他的蛇毒金屬蛋白酶。利用azocasein作為受質,我們發現該蛋白具有酵素活性,其活性能被EDTA或phenanthroline所抑制,但無法被PMSF所抑制,故該蛋白屬於蛇毒金屬蛋白酶。我們將之命名為triflamp (a metalloproteinase from Trimeresurus flavoviridis)。此外,triflamp為一種?纖維蛋白原酶。從人體血小板與嗜中性白血球的實驗發現,triflamp頗具選擇性的抑制與醣蛋白Ib?(GPIb?有關之血小板凝集作用。此外,triflamp能抑制經由PSGL-1與selectin所造成之嗜中性白血球彼此間的黏附作用。經由細胞混合實驗發現,triflamp作用於嗜中性白血球即已足夠抑制嗜中性白血球與血小板之間的黏附作用。Triflamp的這種抗附著作用乃是隨著劑量或作用時間的增加而加強。經流式細胞儀的分析發現,triflamp會明顯減少嗜中性白血球上PSGL-1以及血小板上醣蛋白Ibㄙ漯穛{。西方點墨法證實PSGL-1與醣蛋白Ibㄖ′配riflamp的受質。Triflamp可藉由切除PSGL-1來抑制嗜中性白血球對P-selectin的附著。Triflamp分解PSGL-1的方式與cathepsin G不同。除了PSGL-1的N端外,triflamp應有其他的分解作用點。Phenanthroline能抑制triflamp對PSGL-1之分解。此外,triflamp不會造成嗜中性白血球釋放cathepsin G。值得注意的是,當血小板先以triflamp處理過後,它們仍能與被活化劑如PAF或fMLP刺激的嗜中性白血球黏附,這顯示出triflamp分解血小板上醣蛋白Ibㄙ漣@用並不能影響嗜中性白血球與血小板的黏附。換言之,分解PSGL-1才是其作用機轉。
Triflamp的發現為腹蛇科的蛇毒金屬蛋白酶在抑制血球細胞間的作用上提供一種新的角色,亦即它或釵頃蝷O能應用為抗發炎藥物。然而在人類全血樣本中,即使高達6微克/毫升的triflamp並無法分解嗜中性白血球上的PSGL-1與血小板的醣蛋白IbㄐC人類血液中的?-巨分子球蛋白(?-macroglobulin)能有效中和 triflamp分解PSGL-1、醣蛋白Ib˙P纖維蛋白原的能力。根據分解azocasein的實驗去定量triflamp之酵素活性顯示出,從化學計量學的角度而言,大約一莫耳的人類?-巨分子球蛋白能中和一莫耳triflamp的酵素活性。SDS-膠體電泳實驗顯示,triflamp能在所謂的誘餌區(bait-region)將?-巨分子球蛋白切開。西方點墨法證實,triflamp會與被切下的?-巨分子球蛋白之C端片段形成數種高分子量的複合物。在大量的親核性化合物methylamine的競爭下,triflamp的酵素活性就不被?-巨分子球蛋白所抑制。活體實驗發現,小鼠嗜中性白血球上PSGL-1的表現量不被triflamp所影響。然而,由小鼠血液分離的嗜中性白血球上的PSGL-1與血小板的醣蛋白Ibㄓ敞鉧Dtriflamp所分解。該結果顯示出,一如發生於人類血液樣本上,小鼠血清中的成分應能中和triflamp的酵素活性。?-巨分子球蛋白-triflamp複合物的形成能合理解釋為何triflamp在人類全血樣本與動物模式下會失去酵素活性。
在探討抗血栓蛇毒蛋白對嗜中性白血球之細胞附著因子的影響之模式中,期能開發以抗附著理論為基礎的抗發炎藥物提供一個全新且具潛力的研究方向。適當的藥物篩選模式能尋找出具有高度專一性的產物。雖然蛇毒金屬蛋白酶能應用成為一藥理學研究之工具,但由於動物活體之血液中存在有內生性蛋白酶抑制劑(如?-巨分子球蛋白),使此類蛇毒金屬蛋白酶在藥物開發上難以應用。釐清各類蛇毒金屬蛋白酶與內生性蛋白酶抑制劑的作用,將有助於這類酵素蛋白的應用。此外,研究具有抗附著弁鄋漣C分子量蛇毒蛋白,如disintegrin,或蛇毒中其他非酵素的成分在抗發�靉的角色應是努力的方向。
Disintegrins are a group of Arg(or Lys)-Gly-Asp-containing snake venom proteins which inhibit platelet aggregation via the blockade of ΖIbβ3 integrin. We first studied the effect of rhodostomin, a disintegrin purified from the venom of Calloselasma rhodostoma, on the functions of neutrophils. By flow cytometric analysis of whole blood, we found that rhodostomin interacted with leukocytes of the myeloid and monocytic lineage as well as with platelets. The binding of rhodostomin to neutrophils was dose-dependent and saturable, and its binding was increased in PMA- and fMLP-stimulated neutrophils. EDTA did not inhibit the binding of rhodostomin. In addition, bound rhodostomin was not internalized. Soluble fibrinogen, a natural ligand of Mac-1 (CD11b/CD18, Κβ2), and the peptide, GRGDS, inhibited the binding of rhodostomin to PMA-activated neutrophils, while 7E3, a monoclonal antibody (mAb) raised against β3 integrin, or mAbs raised against Κ and β2 integrin did not. Rhodostomin blocked the Mac-1-dependent adhesion of neutrophils to immobilized fibrinogen, in parallel with decreasing the production of superoxide from adherent neutrophils. These data indicate that rhodostomin binds to activated neutrophils in an RGD-dependent manner, blocks the adhesion of activated neutrophils to fibrinogen and attenuates superoxide production, suggesting that rhodostomin may have anti-inflammatory activity.
Besides disintegrins, other biologically active components from Viperidae venoms specifically affect cell-matrix interactions and have been utilized for developing anti-adhesive therapy as the anti-thrombotic and anti-angiogenic agents. Utilizing platelet aggregometry coupled with flow cytometry, we first found that a metalloproteinase isolated from the venom of Trimeresurus flavoviridis, termed triflamp, inhibited heterotypic adhesion between platelets and neutrophils in whole blood samples. Triflamp is a monomeric glycoprotein with a molecular weight of ~28 kDa. Triflamp has a N-terminal amino acid sequence homologous to other venom metalloproteinases isolated from T. flavoviridis. The enzymatic activity of triflamp towards azocasein was inhibited by EDTA and phenanthroline but not by PMSF. Moreover, triflamp is a pure ?fibrinogenase. Studies aimed at determining the nature of triflamp in affecting platelets or neutrophils revealed a selective inhibitory activity to glycoprotein (GP) Ib?dependent platelet aggregation and P-selectin glycoprotein ligand-1 (PSGL-1)- dependent neutrophil homotypic aggregation, indicating that its effects are rather specific. Coincubation studies demonstrate that direct interaction of triflamp with neutrophils is sufficient to inhibit the formation of neutrophil-platelet complexes. Its anti-adhesive effect is in a concentration- and incubation time-dependent manner. Triflamp reduces the expression of PSGL-1 on neutrophils and GPIb?on platelets as probed by flow cytometry. As judged by Western blotting, GPIb?on platelets and PSGL-1 on neutrophils are the substrates of triflamp. Moreover, triflamp disrupts P-selectin-mediated adhesion by cleaving PSGL-1 from the neutrophil surface. There are obvious differences regarding PSGL-1 proteolysis by triflamp and cathepsin G. Besides the NH2-terminus of PSGL-1, other sites are truncated by triflamp. The inhibitory effect of triflamp on PSGL-1 expression was blocked by pretreatment with a metalloproteinase inhibitor, phenanthroline. However, triflamp-treated platelets fully kept the ability for binding to PAF- or fMLP-stimulated neutrophils. Degradation of platelet GPIb?by triflamp did not interfere with neutrophil-platelet adhesion. Its effect on neutrophil PSGL-1 appears to be a critical factor for its inhibition on neutrophil-platelet interaction.
This study on triflamp revealed the novel role of venom metalloproteinase from Viperidae in affecting the blood cell-cell interactions, thus offering a potential approach for further exploration of anti-inflammatory agents. In human whole blood preparation, however, triflamp (6 μg/ml) failed to cleave neutrophil PSGL-1 and platelet GPIb? Human ?-macroglobulin (?M) was mainly responsible for the neutralization of the proteolytic effects of triflamp on PSGL-1, GPIb?and fibrinogen. Human ?M neutralized triflamp at a stoichiometry about 1:1 (molar basis) as determined by azocaseinolysis. SDS-PAGE analysis revealed that triflamp cleaved the bait-region of ?M. Western blot demonstrated that triflamp interacted with the C-terminal half-subunits of truncated ?M resulting in the formation of high-molecular-weight species of ?M-triflamp complexes. In the presence of a competing nucleophile, methylamine, the proteolytic activity of triflamp was conserved. In vivo we found that mice neutrophils were resistant to the cleavage of PSGL-1 by triflamp. However, mouse PSGL-1 and GPIb?were susceptible to be cleaved by triflamp in washed mouse neutrophil and platelet preparation, respectively. Similarly, mouse serum was also responsible for the inactivation of the proteolytic activity of triflamp. This study provides direct evidences for the reasonable explanation regarding the reduced proteolytic activity of triflamp toward its substrates in whole blood preparation and in vivo model.
Taken together, our data clearly show that the anti-adhesive effects of anti-thrombotic snake venom proteins on neutrophils may become a potentially pharmacological approach for the development of anti-inflammatory agents. A suitable bioassay is helpful for screening specific components from venom mixture. The application of triflamp in vivo is restricted because of being inhibited by endogenous proteinase inhibitors. Dissecting the interactons between snake venom metalloproteinases and endogenous proteinase inhibitors is attempted. Understanding the effect and binding targets of disintegrins on neutrophils and searching other potential anti-adhesive components from snake venom are further tasks.
Contents

Abbreviation …………………………………………………………………VII-VIII

摘要 ……………………………………………………………………………. IX-XI

Abstract ……………………………………………………………………..XIII-XV

CHAPTER 1
Introduction: Viper Venom Proteins, Leukocyte Adhesion
Molecules and Anti-adhesive Therapy…………………………………………….1

CHAPTER 2
Rhodostomin, a Disintegrin, Inhibits Adhesion of Neutrophils
to Fibrinogen and Attenuates Superoxide Production ……………………….... 11

CHAPTER 3
Effects of a Snake Venom Metalloproteinase, Triflamp, on
Platelet Aggregation, Platelet-neutrophil and Neutrophil-
neutrophil Interactions: Involvement of Platelet GPIb?and
Neutrophil PSGL-1 …………………………………………………………….... 29

CHAPTER 4
Triflamp, a Snake Venom Metalloproteinase Reduces
Neutrophil-platelet Adhesion through Proteolysis of PSGL-1
but not Glycoprotein Ib?………………………………………………………... 51

CHAPTER 5
Inhibitory Effects of Human ?-Macroglobulin and Mouse
Serum on the PSGL-1 and Glycoprotein Ib?Proteolysis
by a Snake Venom Metalloproteinase, Triflamp ………………………………. 71

CHAPTER 6
Synopsis and Future Directions: Perspectives on the Potentialities
of Anti-thrombotic Snake Venom Proteins for Anti-adhesive
Therapy towards Neutrophils …………………………………………………... 87

Publication List ………………………………………………………………….. 93
Chapter 1

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42. Tseng YL, Lee CJ, Huang TF. Effects of a snake venom metalloproteinase, triflamp, on platelet aggregation, platelet-neutrophil and neutrophil-neutrophil interactions: involvement of platelet GPIb?and neutrophil PSGL-1. Thromb Haemost 2004; 91: 315-24.
43. Tseng YL, Lee CJ, Hsu CC, Huang TF. Triflamp, a snake venom metalloproteinase reduces neutrophil-platelet adhesion through proteolysis of PSGL-1 but not glycoprotein Ib? Thromb Haemost 2004; 91: 1177-85.
44. Tseng YL, Wu WB, Hsu CC, Peng HC, Huang TF. Inhibitory effects of human ?-Macroglobulin and mouse serum on the PSGL-1 and glycoprotein Ib?proteolysis by a snake venom metalloproteinase, triflamp. Toxicon 2004; 43: 769-77.


Chapter 2

1. Farb A, Sangiorgi G, Carter AJ, Wally VM, Edwards WD, Schwartz RS, Virmani R. Pathology of acute and chronic coronary stenting in humans. Circulation 1999; 99: 44-52.
2. Kuijper PH, Gallardo Torres HI, Lammers JW, Sixma JJ, Koenderman L, Zwaginga JJ. Platelet and fibrin deposition at the damaged vessel wall: cooperative substrates for neutrophil adhesion under flow conditions. Blood 1997; 89:166-75.
3. Weiss SJ. Tissue destruction by neutrophils. N Engl J Med 1989; 320: 365-76.
4. Diamond MS, Springer TA. A subpopulation of Mac-1 (CD11b/CD18) molecules mediates neutrophil adhesion to ICAM-1 and fibrinogen. J Cell Biol 1993; 120: 545-56.
5. Rogers C, Edelman ER, Simon DI. A mAb to the β2-leukocyte integrin Mac-1 (CD11b/CD18) reduces intimal thickening after angioplasty or stent implantation in rabbits. Proc Natl Acad Sci USA 1998; 95:10134-9.
6. Golino P, Ambrosio G, Ragni M, Cirillo P, Esposito N, Willerson JT, Rothlein R, Petrucci L, Condorelli M, Chiariello M, Buja LM. Inhibition of leucocyte and platelet adhesion reduces neointimal hyperplasia after arterial injury. Thromb Haemost 1997; 77: 783-8.
7. Coller BS. Potential non-glycoprotein IIb/IIIa effects of abciximab. Am Heart J 1999; 138: S1-5.
8. Mickelson JK, Ali MN, Kleiman NS, Lakkis NM, Chow TW, Hughes BJ, Smith CW. Chimeric 7E3 Fab (ReoPro) decreases detectable CD11b on neutrophils from patients undergoing coronary angioplasty. J Am Coll Cardiol 1999; 33: 97-106.
9. Topol EJ, Califf RM, Weisman HF, Ellis SG, Tcheng JE, Worley S, Ivanhoe R, George BS, Fintel D, Weston M. Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. The EPIC Investigators. Lancet 1994; 343: 881-6.
10. Simon DI, Xu H, Ortlepp S, Rogers C, Rao NK. 7E3 monoclonal antibody directed against the platelet glycoprotein IIb/IIIa cross-reacts with the leukocyte integrin Mac-1 and blocks adhesion to fibrinogen and ICAM-1. Arterioscler Thromb Vasc Biol 1997; 17: 528-35.
11. Huang TF. What have snakes taught us about integrins? Cell Mol Life Sci 1998; 54: 527-40.
12. Yeh CH, Peng HC, Huang TF. Accutin, a new disintegrin, inhibits angiogenesis in vitro and in vivo by acting as integrin ㄇβ3 antagonist and inducing apoptosis. Blood 1998; 92: 3268-76.
13. Sheu JR, Lin CH, Chung JL, Teng CM, Huang TF. Triflavin, an Arg-Gly-Asp-containing antiplatelet peptide inhibits cell-substratum adhesion and melanoma cell-induced lung colonization. Jpn J Cancer Res 1992; 83: 885-93.
14. Frishman WH, Burns B, Atac B, Alturk N, Altajar B, Lerrick K. Novel antiplatelet therapies for treatment of patients with ischemic heart disease: inhibitors of the platelet glycoprotein IIb/IIIa integrin receptor. Am Heart J 1995; 130: 877-92.
15. Liu CZ, Hur BT, Shen MC, Huang TF. Measurement of glycoprotein IIb-IIIa blockade by flow cytometry with fluorescein isothiocyanate-conjugated crotavirin, a member of disintegrins. Thromb Haemost 1996; 76: 585-91.
16. Juliano D, Wang Y, Marcinkiewicz C, Rosenthal LA, Stewart GJ, Niewiarowski S. Disintegrin interaction with ㄇβ3 integrin on human umbilical vein endothelial cells: expression of ligand-induced binding site on β3 subunit. Exp Cell Res 1996; 225: 132-42.
17. Huang TF, Wu YJ, Ouyang C. Characterization of a potent platelet aggregation inhibitor from Agkistrodon rhodostoma snake venom. Biochim Biophys Acta 1987; 925: 248-57.
18. Cantinieaux B, Hariga C, Courtoy P, Hupin J, Fondu P. Staphylococcus aureus phagocytosis. A new cytofluorometric method using FITC and paraformaldehyde. J Immunol Methods 1989; 121: 203-8.
19. Masumoto A, Hemler ME. Multiple activation states of VLA-4. Mechanistic differences between adhesion to CS1/fibronectin and to vascular cell adhesion molecule-1. J Biol Chem 1993; 268: 228-34.
20. Lowell CA, Fumagalli L, Berton G. Deficiency of Src family kinase p59/61hck and p58c-fgr results in defective adhesion-dependent neutrophil functions. J Cell Biol 1996; 133: 895-910.
21. Celi A, Lorenzet R, Furie B, Furie BC. Platelet-leukocyte-endothelial cell interaction on the blood vessel wall. Semin Hematol 1997; 34: 327-35.
22. Gould RJ, Polokoff MA, Friedman PA, Huang TF, Holt JC, Cook JJ, Niewiarowski S. Disintegrins: a family of integrin inhibitory proteins from viper venoms. Proc Soc Exp Biol Med 1990; 195: 168-71.
23. Altieri DC, Edgington TS. A monoclonal antibody reacting with distinct adhesion molecules defines a transition in the functional state of the receptor CD11b/CD18 (Mac-1). J Immunol 1988; 141: 2656-60.
24. Nathan CF. Neutrophil activation on biological surfaces. Massive secretion of hydrogen peroxide in response to products of macrophages and lymphocytes. J Clin Invest 1987; 80: 1550-60.
25. Rinder HM, Bonan JL, Rinder CS, Ault KA, Smith BR. Activated and unactivated platelet adhesion to monocytes and neutrophils. Blood 1991; 78: 1760-9.
26. Marcinkiewicz C, Calvete JJ, Vijay-Kumar S, Marcinkiewicz MM, Raida M, Schick P, Lobb RR, Niewiarowski S. Structural and functional characterization of EMF10, a heterodimeric disintegrin from Eristocophis macmahoni venom that selectively inhibits ?β1 integrin. Biochemistry 1999; 38: 13302-9.
27. Marcinkiewicz C, Calvete JJ, Marcinkiewicz MM, Raida M, Vijay-Kumar S, Huang Z, Lobb RR, Niewiarowski S. EC3, a novel heterodimeric disintegrin from Echis carinatus venom, inhibits ? and ? integrins in an RGD-independent manner. J Biol Chem 1999; 274: 12468-73.
28. Wierzbicka-Patynowski I, Niewiarowski S, Marcinkiewicz C, Calvete JJ, Marcinkiewicz MM, McLane MA. Structural requirements of echistatin for the recognition of ㄇβ3 and ?β1 integrins. J Biol Chem 1999; 274: 37809-14.
29. Smith JB, Theakston RD, Coelho AL, Barja-Fidalgo C, Calvete JJ, Marcinkiewicz C. Characterization of a monomeric disintegrin, ocellatusin, present in the venom of the Nigerian carpet viper, Echis ocellatus. FEBS Lett 2002; 512: 111-5.
30. Taniguchi-Sidle A, Isenman DE. Mutagenesis of the Arg-Gly-Asp triplet in human complement component C3 does not abolish binding of iC3b to the leukocyte integrin complement receptor type III (CR3, CD11b/CD18). J Biol Chem 1992; 267: 635-43.
31. Wright SD, Reddy PA, Jong MT, Erickson BW. C3bi receptor (complement receptor type 3) recognizes a region of complement protein C3 containing the sequence Arg-Gly-Asp. Proc Natl Acad Sci USA 1987; 84: 1965-8.
32. Harris ES, McIntyre TM, Prescott SM, Zimmerman GA. The leukocyte integrins. J Biol Chem 2000; 275: 23409-12.
33. Sussmuth SD, Muscholl-Silberhorn A, Wirth R, Susa M, Marre R, Rozdzinski E. Aggregation substance promotes adherence, phagocytosis, and intracellular survival of Enterococcus faecalis within human macrophages and suppresses respiratory burst. Infect Immun 2000; 68: 4900-6.
34. Zhou L, Lee DH, Plescia J, Lau CY, Altieri DC. Differential ligand binding specificities of recombinant CD11b/CD18 integrin I-domain. J Biol Chem 1994; 269: 17075-9.
35. Lishko VK, Yakubenko VP, Hertzberg KM, Grieninger G, Ugarova TP. The alternatively spliced ΒC domain of human fibrinogen-420 is a novel ligand for leukocyte integrins Κβ2 and Φβ2. Blood 2001; 98: 2448-55.
36. Coelho AL, De Freitas MS, Mariano-Oliveira A, Oliveira-Carvalho AL, Zingali RB, Barja-Fidalgo C. Interaction of disintegrins with human neutrophils induces cytoskeleton reorganization, focal adhesion kinase activation, and extracellular- regulated kinase-2 nuclear translocation, interfering with the chemotactic function. FASEB J 2001; 15: 1643-5.
37. Yan SR, Novak MJ. Diverse effects of neutrophil integrin occupation on respiratory burst activation. Cell Immunol 1999; 195: 119-26.
38. Gresham HD, Goodwin JL, Allen PM, Anderson DC, Brown EJ. A novel member of the integrin receptor family mediates Arg-Gly-Asp-stimulated neutrophil phagocytosis. J Cell Biol 1989; 108: 1935-43.
39. Ishibashi Y, Claus S, Relman DA. Bordetella pertussis filamentous hemagglutinin interacts with a leukocyte signal transduction complex and stimulates bacterial adherence to monocyte CR3 (CD11b/CD18). J Exp Med 1994; 180: 1225-33.


Chapter 3

1. McEver RP. Adhesive interactions of leukocytes, platelets, and the vessel wall during hemostasis and inflammation. Thromb Haemost 2001; 86: 746-56.
2. Evangelista V, Manarini S, Sideri R, Rotondo S, Martelli N, Piccoli A, Totani L, Piccardoni P, Vestweber D, de Gaetano G, Cerletti C. Platelet/polymorphonuclear leukocyte interaction: P-selectin triggers protein-tyrosine phosphorylation-dependent CD11b/CD18 adhesion: role of PSGL-1 as a signaling molecule. Blood 1999; 93: 876-85.
3. Nagata K, Tsuji T, Todoroki N, Katagiri Y, Tanoue K, Yamazaki H, Hanai N, Irimura T. Activated platelets induce superoxide anion release by monocytes and neutrophils through P-selectin (CD62). J Immunol 1993; 151: 3267-73.
4. Renesto P, Chignard M. Enhancement of cathepsin G-induced platelet activation by leukocyte elastase: consequence for the neutrophil-mediated platelet activation. Blood 1993; 82: 139-44.
5. Valles J, Santos MT, Marcus AJ, Safier LB, Broekman MJ, Islam N, Ullman HL, Aznar J. Downregulation of human platelet reactivity by neutrophils. Participation of lipoxygenase derivatives and adhesive proteins. J Clin Invest 1993; 92: 1357-65.
6. Palabrica T, Lobb R, Furie BC, Aronovitz M, Benjamin C, Hsu YM, Sajer SA, Furie B. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 1992; 359: 848-51.
7. Rinder CS, Bonan JL, Rinder HM, Mathew J, Hines R, Smith BR. Cardiopulmonary bypass induces leukocyte-platelet adhesion. Blood 1992; 79: 1201-05.
8. Bonomini M, Stuard S, Carreno MP, Settefrati N, Santarelli P, Haeffner-Cavaillon N, Albertazzi A. Neutrophil reactive oxygen species production during hemodialysis: role of activated platelet adhesion to neutrophils through P-selectin. Nephron 1997; 75: 402-11.
9. Kupatt C, Habazettl H, Hanusch P, Wichels R, Hahnel D, Becker BF, Boekstegers P. c7E3Fab reduces postischemic leukocyte-thrombocyte interaction mediated by fibrinogen. Implications for myocardial reperfusion injury. Arterioscler Thromb Vasc Biol 2000; 20: 2226-32.
10. Serrano CV, Jr., Ramires JA, Venturinelli M, Arie S, D''Amico E, Zweier JL, Pileggi F, da Luz PL. Coronary angioplasty results in leukocyte and platelet activation with adhesion molecule expression. Evidence of inflammatory responses in coronary angioplasty. J Am Coll Cardiol 1997; 29: 1276-83.
11. Huang TF. What have snakes taught us about integrins? Cell Mol Life Sci 1998; 54: 527-40.
12. Lee LW, Peng HC, Ko WC, Hung WC, Su CH, Lin CH, Huang TF, Yen MH, Sheu JR. Triflavin potentiates the antiplatelet activity of platelet activating factor receptor antagonist on activated neutrophil-induced platelet aggregation. Eur J Pharmacol 1999; 364: 239-46.
13. Konstantopoulos K, Neelamegham S, Burns AR, Hentzen E, Kansas GS, Snapp KR, Berg EL, Hellums JD, Smith CW, McIntire LV, Simon SI. Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and β2-integrin. Circulation 1998; 98: 873-82.
14. Kinsella JL, Ralph LJ, Ryan MF. A preliminary analysis of proteolytic activity of excretory- secretory products from Cyathostominea. Vet Parasitol 2002; 107: 73-83.
15. Languino LR, Plescia J, Duperray A, Brian AA, Plow EF, Geltosky JE, Altieri DC. Fibrinogen mediates leukocyte adhesion to vascular endothelium through an ICAM-1-dependent pathway. Cell 1993; 73: 1423-34.
16. Liu CZ, Hur BT, Huang TF. Measurement of glycoprotein IIb/IIIa blockade by flow cytometry with fluorescein isothiocyanate-conjugated crotavirin, a member of disintegrins. Thromb Haemost 1996; 76: 585-91.
17. Taylor AD, Neelamegham S, Hellums JD, Smith CW, Simon SI. Molecular dynamics of the transition from L-selectin- to β2-integrin-dependent neutrophil adhesion under defined hydrodynamic shear. Biophys J 1996; 71: 3488-500.
18. Clemetson KJ, Clemetson JM. Platelet collagen receptors. Thromb Haemost 2001; 86: 189-97.
19. Simon DI, Chen Z, Xu H, Li CQ, Dong J, McIntire LV, Ballantyne CM, Zhang L, Furman MI, Berndt MC, Lopez JA. Platelet glycoprotein Ib?is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med 2000; 192: 193-204.
20. Miyata T, Takeya H, Ozeki Y, Arakawa M, Tokunaga F, Iwanaga S, Omori-Satoh T. Primary structure of hemorrhagic protein, HR2a, isolated from the venom of Trimeresurus flavoviridis. J Biochem 1989; 105: 847-53.
21. Iha M, Qi ZQ, Kannki T, Tomihara Y, Yonaha K. The primary structure of a hemorrhagic factor, HR2b, from the venom of Okinawa habu (Trimeresurus flavoviridis). Toxicon 1995; 33: 229-39.
22. Takeya H, Arakawa M, Miyata T, Iwanaga S, Omori-Satoh T. Primary structure of H2-proteinase, a non-hemorrhagic metalloproteinase, isolated from the venom of the Habu snake, Trimeresurus flavoviridis. J Biochem 1989; 106: 151-7.
23. Kishimoto M, Takahashi T. Molecular cloning and sequence analysis of cDNA encoding flavoridin, a disintegrin from the venom of Trimeresurus flavoviridis. Toxicon 2002; 40: 1033-40.
24. Kornalik F. The influence of snake venom proteins on blood coagulation. In: Snake Toxins. Pergamon Press 1991; 323-83.
25. Greco NJ, Jamieson GA. High and moderate affinity pathways for thrombin-induced platelet activation. Proc Soc Exp Biol Med 1991; 198: 792-9.
26. Snapp KR, Ding H, Atkins K, Warnke R, Luscinskas FW, Kansas GS. A novel P-selectin glycoprotein ligand-1 monoclonal antibody recognizes an epitope within the tyrosine sulfate motif of human PSGL-1 and blocks recognition of both P- and L-selectin. Blood 1998; 91: 154-64.
27. De Luca M, Dunlop LC, Andrews RK, Flannery JV, Jr., Ettling R, Cumming DA, Veldman GM, Berndt MC. A novel cobra venom metalloproteinase, mocarhagin, cleaves a 10-amino acid peptide from the mature N terminus of P-selectin glycoprotein ligand receptor, PSGL-1, and abolishes P-selectin binding. J Biol Chem 1995; 270: 26734-7.
28. Ward CM, Andrews RK, Smith AI, Berndt MC. Mocarhagin, a novel cobra venom metallo- proteinase, cleaves the platelet von Willebrand factor receptor glycoprotein Ib? Identification of the sulfated tyrosine/anionic sequence Tyr-276-Glu-282 of glycoprotein Ib?as a binding site for von Willebrand factor and alpha-thrombin. Biochemistry 1996; 35: 4929-38.
29. Matsui T, Fujimura Y, Titani K. Snake venom proteases affecting hemostasis and thrombosis. Biochim Biophys Acta 2000; 1477: 146-56.
30. Braud S, Bon C, Wisner A. Snake venom proteins acting on hemostasis. Biochimie 2000; 82: 851-9.
31. Gutierrez JM, Rucavado A. Snake venom metalloproteinases: their role in the pathogenesis of local tissue damage. Biochimie 2000; 82: 841-50.
32. Wu WB, Peng HC, Huang TF. Crotalin, a vWF and GP Ib cleaving metalloproteinase from venom of Crotalus atrox. Thromb Haemost 2001; 86:1501-11.
33. Huang TF, Chang MC, Teng CM. Antiplatelet protease, kistomin, selectively cleaves human platelet glycoprotein Ib. Biochim Biophys Acta 1993; 1158: 293-9.
34. Bee A, Theakston RD, Harrison RA, Carter SD. Novel in vitro assays for assessing the haemorrhagic activity of snake venoms and for demonstration of venom metalloproteinase inhibitors. Toxicon 2001; 39: 1429-34.
35. Jakson SP, Schoenwaelder SM. Antiplatelet therapy: in search of the ‘magic bullet’. Nature Rev Drug Discovery 2003; 2: 1-15.
36. Smith CW. Possible steps involved in the transition to stationary adhesion of rolling neutrophils: a brief review. Microcirculation 2000; 7: 385-94.
37. Spangenberg P, Redlich H, Bergmann I, Losche W, Gotzrath M, Kehrel B. The platelet glycoprotein IIb/IIIa complex is involved in the adhesion of activated platelets to leukocytes. Thromb Haemost 1993; 70: 514-21.
38. Ostrovsky L, King AJ, Bond S, Mitchell D, Lorant DE, Zimmerman GA, Larsen R, Niu XF, Kubes P. A juxtacrine mechanism for neutrophil adhesion on platelets involves platelet-activating factor and a selectin-dependent activation process. Blood 1998; 91: 3028-36.
39. Taniuchi Y, Kawasaki T, Fujimura Y, Suzuki M, Titani K, Sakai Y, Kaku S, Hisamichi N, Satoh N, Takenaka T, . Flavocetin-A and -B, two high molecular mass glycoprotein Ib binding proteins with high affinity purified from Trimeresurus flavoviridis venom, inhibit platelet aggregation at high shear stress. Biochim Biophys Acta 1995; 1244: 331-8.
40. Li R, Xie J, Kantor C, Koistinen V, Altieri DC, Nortamo P, Gahmberg CG. A peptide derived from the intercellular adhesion molecule-2 regulates the avidity of the leukocyte integrins CD11b/CD18 and CD11c/CD18. J Cell Biol 1995; 129: 1143-53.
41. Anai K, Sugiki M, Yoshida E, Maruyama M. Inhibition of a snake venom hemorrhagic metalloproteinase by human and rat ?macroglobulins. Toxicon 1998; 36: 1127-39.
42. Svoboda P, Meier J, Freyvogel TA. Purification and characterization of three ?-antiplasmin and ?-macroglobulin inactivating enzymes from the venom of the Mexican west coast rattlesnake (Crotalus basiliscus). Toxicon 1995; 33: 1331-46.


Chapter 4

1. Ogura H, Kawasaki T, Tanaka H, Koh T, Tanaka R, Ozeki Y, Hosotsubo H, Kuwagata Y, Shimazu T, Sugimoto H. Activated platelets enhance microparticle formation and platelet-leukocyte interaction in severe trauma and sepsis. J Trauma 2001; 50: 801-9.
2. Ott I, Neumann F-J, Gawaz M, Schmitt M, Schoemig A. Increased neutrophil-platelet adhesion in patients with unstable angina. Circulation 1996; 94: 1239-46.
3. Rinder CS, Bonan JL, Rinder HM, Mathew J, Hines R, Smith BR. Cardiopulmonary bypass induces leukocyte-platelet adhesion. Blood 1992; 79: 1201-5.
4. Tschoepe D, Rauch U, Schwippert B. Platelet-leukocyte-cross-talk in diabetes mellitus. Horm Metabolic Res 1997; 29: 631-5.
5. Palabrica T, Lobb R, Furie BC, Aronovitz M, Benjamin C, Hsu YM, Sajer SA, Furie B. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 1992; 359: 848-51.
6. McEver RP. Adhesive interactions of leukocytes, platelets, and the vessel wall during hemostasis and inflammation. Thromb Haemost 2001; 86: 746-56.
7. Moore KL, Patel KD, Bruehl RE, Li F, Johnson DA, Lichenstein HS, Cummings RD, Bainton DF, McEver RP. P-selectin glycoprotein ligand-1 mediates rolling of human neutrophils on P-selectin. J Cell Biol 1995; 128: 661-71.
8. Diacovo TG, Roth SJ, Buccola JM, Bainton DF, Springer TA. Neutrophil rolling, arrest, and transmigration across activated, surface-adherent platelets via sequential action of P-selectin and the β2-integrin CD11b/CD18. Blood 1996; 88: 146-57.
9. Evangelista V, Manarini S, Rotondo S, Martelli N, Polischuk R, McGregor JL, de Gaetano G, Cerletti C. Platelet/polymorphonuclear leukocyte interaction in dynamic conditions: evidence of adhesion cascade and cross talk between P-selectin and the β2-integrin CD11b/CD18. Blood 1996; 88: 4183-94.
10. Hidari KI, Weyrich AS, Zimmerman GA, McEver RP. Engagement of P-selectin glycoprotein ligand-1 enhances tyrosine phosphorylation and activates mitogen-activated protein kinases in human neutrophils. J Biol Chem 1997; 272: 28750-6.
11. Evangelista V, Manarini S, Sideri R, Rotondo S, Martelli N, Piccoli A, Totani L, Piccardoni P, Vestweber D, de Gaetano G, Cerletti C. Platelet/polymorphonuclear leukocyte interaction: P-selectin triggers protein-tyrosine phosphorylation-dependent CD11b/CD18 adhesion: role of PSGL-1 as a signaling molecule. Blood 1999; 93: 876-85.
12. Nagata K, Tsuji T, Todoroki N, Katagiri Y, Tanoue K, Yamazaki H, Hanai N, Irimura T. Activated platelets induce superoxide anion release by monocytes and neutrophils through P-selectin (CD62). J Immunol 1993; 151: 3267-73.
13. Ruf A, Patscheke H. Platelet-induced neutrophil activation: platelet-expressed fibrinogen induces the oxidative burst in neutrophils by an interaction with CD11C/CD18. Br J Haematol 1995; 90: 791-6.
14. Ward CM, Andrews RK, Smith AI, Berndt. Mocarhagin, a novel cobra venom metalloproteinase, cleaves the platelet von Willebrand factor receptor glycoprotein Ib? identification of the sulfate tyrosine/anionic sequence Tyr-276-Glu-282 of glycoprotein Ib?as abinding site for von Willebrand factor and ?thrombin. Biochemistry 1996; 35: 4929-4938.
15. Simon DI, Chen Z, Xu H, Li CQ, Dong J, McIntire LV, Ballantyne CM, Zhang L, Furman MI, Berndt MC, Lopez JA. Platelet glycoprotein Ib?is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med 2000; 192: 193-204.
16. Tseng YL, Lee CJ, Huang TF. Effects of a snake venom metalloproteinase, triflamp, on platelet aggregation, platelet-neutrophil and neutrophil-neutrophil interactions: involvement of platelet GPIb?and neutrophil PSGL-1. Thromb Haemost 2004; 91: 315-24.
17. Liu CZ, Hur BT, Huang TF. Measurement of glycoprotein IIb/IIIa blockade by flow cytometry with fluorescein isothiocyanate-conjugated crotavirin, a member of disintegrins. Thromb Haemost 1996; 76: 585-91.
18. Nakajima K, Powers JC, Ashe BM, Zimmerman M. Mapping the extended substrate binding site of cathepsin G and human leukocyte elastase. Studies with peptide substrates related to the alpha 1-protease inhibitor reactive site. J Biol Chem 1979; 254: 4027-32.
19. Konstantopoulos K, Neelamegham S, Burns AR, Hentzen E, Kansas GS, Snapp KR, Berg EL, Hellums JD, Smith CW, McIntire LV, Simon SI. Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and β2-integrin. Circulation 1998; 98: 873-82.
20. Epperson TK, Patel KD, McEver RP, Cummings RD. Noncovalent association of P-selectin glycoprotein ligand-1 and minimal determinants for binding to P-selectin. J Biol Chem 2000; 275: 7839-53.
21. Renesto P, Halbwachs-Mecarelli L, Bessou G, Balloy V, Chignard M. Inhibition of neutrophil- endothelial cell adhesion by a neutrophil product, cathepsin G. J Leukoc Biol 1996; 59: 855-63.
22. Gardiner EE, De Luca M, McNally T, Michelson AD, Andrews RK, Berndt MC. Regulation of P-selectin binding to the neutrophil P-selectin counter-receptor P-selectin glycoprotein ligand-1 by neutrophil elastase and cathepsin G. Blood 2001; 98: 1440-7.
23. Li N, Goodall AH, Hjemdahl P. Efficient flow cytometric assay for platelet-leukocyte aggregates in whole blood using fluorescence signal triggering. Cytometry 1999; 35: 154-61.
24. Davenpeck KL, Brummet ME, Hudson SA, Mayer RJ, Bochner BS. Activation of human leukocytes reduces surface P-selectin glycoprotein ligand-1 (PSGL-1, CD162) and adhesion to P-selectin in vitro. J Immunol 2000; 165: 2764-72.
25. De Luca M, Dunlop LC, Andrews RK, Flannery JV, Jr, Ettling R, Cumming DA, Veldman GM, Berndt MC. A novel cobra venom metalloproteinase, mocarhagin, cleaves a 10-amino acid peptide from the mature N terminus of P-selectin glycoprotein ligand receptor, PSGL-1, and abolishes P-selectin binding. J Biol Chem 1995; 270: 26734-7.
26. Peterson DM, Stathopoulos NA, Giorgio TD, Hellums JD, Moake JL. Shear-induced platelet aggregation requires von Willebrand factor and platelet membrane glycoproteins Ib and IIb-IIIa. Blood 1987; 69: 625-8.
27. Hoffmeister KM, Felbinger TW, Falet H, Denis CV, Bergmeier W, Mayadas TN, von Andrian UH, Wagner DD, Stossel TP, Hartwig JH. The clearance mechanism of chilled blood platelets. Cell 2003; 112: 87-97.
28. Li R, Xie J, Kantor C, Koistinen V, Altieri DC, Nortamo P, Gahmberg CG. A peptide derived from the intercellular adhesion molecule-2 regulates the avidity of the leukocyte integrins CD11b/CD18 and CD11c/CD18. J Cell Biol 1995; 129: 1143-53.
29. Hentzen ER, Neelamegham S, Kansas GS, Benanti JA, McIntire LV, Smith CW, Simon SI. Sequential binding of CD11a/CD18 and CD11b/CD18 defines neutrophil capture and stable adhesion to intercellular adhesion molecule-1. Blood 2000; 95: 911-20.
30. Lorant DE, Patel KD, McIntyre TM, McEver RP, Prescott SM, Zimmerman GA. Coexpression of GMP-140 and PAF by endothelium stimulated by histamine or thrombin: a juxtacrine system for adhesion and activation of neutrophils. J Cell Biol 1991; 115: 223-34.
31. Dore M, Burns AR, Hughes BJ, Entman ML, Smith CW. Chemoattractant-induced changes in surface expression and redistribution of a functional ligand for P-selectin on neutrophils. Blood 1996; 87: 2029-37.
32. Lorant DE, McEver RP, McIntyre TM, Moore KL, Prescott SM, Zimmerman GA. Activation of polymorphonuclear leukocytes reduces their adhesion to P-selectin and causes redistribution of ligands for P-selectin on their surfaces. J Clin Invest 1995; 96: 171-82.
33. Lefer AM, Campbell B, Shin YK. Effects of a metalloproteinase that truncates P-selectin glycoprotein ligand on neutrophil-induced cardiac dysfunction in ischemia/reperfusion. J Mol Cell Cardiol 1998; 30: 2561-6.


Chapter 5

1. Tseng YL, Lee CJ, Huang TF. Effects of a snake venom metalloproteinase, triflamp, on platelet aggregation, platelet-neutrophil and neutrophil-neutrophil interactions: involvement of platelet GPIb?and neutrophil PSGL-1. Thromb Haemost 2004; 91: 315-24.
2. Lefer AM, Campbell B, Shin YK. Effects of a metalloproteinase that truncates P-selectin glycoprotein ligand on neutrophil-induced cardiac dysfunction in ischemia/reperfusion. J Mol Cell Cardiol 1998; 30: 2561-6.
4. Sottrup-Jensen L. Alpha-macroglobulins: structure, shape, and mechanism of proteinase complex formation. J Biol Chem 1989; 264: 11539-42.
5. Saidi N, Samel M, Siigur J, Jensen PEH. Lebetase, a ?β)-fibrin(oren)olytic metalloproteinase of Vipera lebetina snake venom, is inhibited by human ?macroglobulins. Biochim Biophys Acta 1999; 1434: 94-102.
6. Souza CT, Moura MB, Magalhaes A, Heneine LGD, Olortegui CC, Diniz CR, Sanchez EF. Inhibition of mutalysin II, a metalloproteinase from bushmaster snake venom by human ?-macroglobulin and rabbit immunoglobulin. Comp Biochem Physiol B Biochem Mol Biol 2001; 130: 155-68.
7. Kawano J, Anai K, Sugiki M, Yoshida E, Maruyama M. Vascular endothelial cell injury induced by Bothrops jararaca venom; non-significance of hemorrhagic metalloproteinase. Toxicon 2002; 40: 1553-62.
8. Yeh CH, Chang MC, Peng HC, Huang TF. Pharmacological characterization and antithrombotic effect of agkistin, a platelet glycoprotein Ib antagonist. Br J Pharmacol 2001; 132: 843-50.
9. Wu WB, Huang TF. Gramicetin: a new agonist that activates platelets via glycoprotein Ib ligation. J Thromb Haemost 2003; 1 (Supplement 1): P1305.
10. Languino LR, Plescia J, Duperray A, Brian AA, Plow EF, Geltosky JE, Altieri DC. Fibrinogen mediates leukocyte adhesion to vascular endothelium through an ICAM-1-dependent pathway. Cell 1993; 73: 1423-34.
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Chapter 6

1. Tseng YL, Lee CJ, Huang TF. Effects of a snake venom metalloproteinase, triflamp, on platelet aggregation, platelet-neutrophil and neutrophil-neutrophil interactions: involvement of platelet GPIb?and neutrophil PSGL-1. Thromb Haemost 2004; 91: 315-24.
2. Miyata T, Takeya H, Ozeki Y, Arakawa M, Tokunaga F, Iwanaga S, Omori-Satoh T. Primary structure of hemorrhagic protein, HR2a, isolated from the venom of Trimeresurus flavoviridis. J Biochem 1989; 105: 847-53.
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4. Takeya H, Arakawa M, Miyata T, Iwanaga S, Omori-Satoh T. Primary structure of H2-proteinase, a non-hemorrhagic metalloproteinase, isolated from the venom of the Habu snake, Trimeresurus flavoviridis. J Biochem 1989; 106: 151-7.
5. Kishimoto M, Takahashi T. Molecular cloning and sequence analysis of cDNA encoding flavoridin, a disintegrin from the venom of Trimeresurus flavoviridis. Toxicon 2002; 40: 1033-40.
6. Tseng YL, Lee CJ, Hsu CC, Huang TF. Triflamp, a snake venom metalloproteinase reduces neutrophil-platelet adhesion through proteolysis of PSGL-1 but not glycoprotein Ib? Thromb Haemost 2004: 91: 1177-85.
7. Simon DI, Chen Z, Xu H, Li CQ, Dong J, McIntire LV, Ballantyne CM, Zhang L, Furman MI, Berndt MC, Lopez JA. Platelet glycoprotein Ib?is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med 2000; 192: 193-204.
8. Tseng YL, Wu WB, Hsu CC, Peng HC, Huang TF. Inhibitory effects of human ?-Macroglobulin and mouse serum on the PSGL-1 and glycoprotein Ib?proteolysis by a snake venom metalloproteinase, triflamp. Toxicon 2004; 43: 769-77.
9. Wu WB, Peng HC, Huang TF. Crotalin, a vWF and GP Ib cleaving metalloproteinase from venom of Crotalus atrox. Thromb Haemost 2001; 86:1501-11.
10. Huang TF, Chang MC, Teng CM. Antiplatelet protease, kistomin, selectively cleaves human platelet glycoprotein Ib. Biochim Biophys Acta 1993; 1158: 293-9.
11. Baramova EN, Shannon JD, Bjarnason JB, Gonias ST, Fox JW. Interaction of hemorrhagic metalloproteinases with human ?-macroglobulin. Biochemistry 1990; 29: 1069-74.
12. Tseng YL, Peng HC, Huang TF. Rhodostomin, a disintegrin, inhibits adhesion of neutrophils to fibrinogen and attenuates superoxide production. J Biomed Sci (in press).
13. Bower K, Djordjevic SP, Andronicos NM, Ranson M. Cell surface antigens of Mycoplasma species bovine group 7 bind to and activate plasminogen. Infect Immun 2001; 69: 1977-82.
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