臺灣博碩士論文加值系統

登革病毒是黃病毒之一，可區分為四個血清型。登革病毒感染可能引起登革出血熱/休克症候(Dengue hemorrhage fever/dengue shock syndrome, DHF/DSS)，一種由登革病毒造成的急性、可能致命的疾病。或者造成登革熱(Dengue fever, DF)，這是一種急性但會自行痊癒的疾病。登革出血熱/休克症候的臨床症狀包括體液流失、血比容上升、血小板減少以及低血容性休克。造成登革出血熱/休克症候的致病機轉尚未被研究清楚。許多證據指出DHF病人的出血現象與血小板減少、凝血系統缺失、以及內皮系統病變等等有關。本論文的主要目標是利用登革病人的檢體以及人類內皮細胞體外培養系統，研究登革病毒以及其引發的抗體反應，對於凝血系統與纖維蛋白溶解系統，以及血管內皮細胞兩部分的影響，以期對於出血的過程和機制有進一步的了解。
我們比較25位登革病人(登革熱或登革出血熱)發病後不同時間的血小板數目、凝血原時間(Prothrombin Time, PT)、活化部份凝血活時間(Activated Partial Thromboplastin Time, APTT)、組織纖溶活化劑(tissue plasminogen activator, tPA) 和纖溶活化劑抑制劑-1(plasminogen activator inhibitor 1, PAI-1)的量。所有的登革出血熱病人在急性期都有血小板減少的情形。除了一個死亡病例以外，其他病人的凝血原時間都正常。而登革出血熱病人在急性期的活化部份凝血活時間有延長的現象，但在登革熱病人則無。此外，在登革出血熱病人急性期可以觀察到組織纖溶活化劑的量有劇烈的上升，此情形在登革熱病人並不存在。而在恢復期，病人體內的組織纖溶活化劑回復至正常範圍，而組織纖溶活化劑抑制劑明顯的上升。在登革出血熱病人急性期的tPA/PAI-1比值明顯地上升，顯示出血症狀可能肇因於凝血系統與纖維蛋白溶解系統活化的不平衡所造成的纖維溶解系統過份活化。而且，住院48小時內的APTT和tPA/PAI-1比值可以作為疾病發展的預測因子。在登革病人體內具有可與纖維溶解原(plasminogen)結合的抗體，這些抗體在體外測試時會抑制纖維溶解(plasmin)的作用，而在體內可能保護他們不與抑制劑結合。而且，抗體對於尿激(urokinase)活化纖維溶解原的功能有加強作用。
另一方面則是研究病毒感染內皮細胞後對細胞功能的影響。登革病毒感染細胞後，可在培養液和細胞內看到病毒效價的上升，並且可偵測到病毒RNA及蛋白質以確定感染。病毒感染會使內皮細胞產生大量的IL-6，但IL-1b的生成不受影響；且在登革出血熱病人體內IL-6也較正常人及登革熱病人明顯的升高。病毒感染之人類內皮細胞亦有tPA產量上升的情形，而PAI-1的產量沒有受影響。病毒引發的tPA產量增加是透過IL-6的作用。利用偵測細胞釋放的TM以及細胞的通透性發現病毒感染本身並不會造成細胞的損傷。然而，感染後的細胞會產生IL-8和RANTES，在登革出血熱病人體內亦有大量的IL-8和RANTES的表現，可能經由吸引白血球到感染的部位而間接地傷害細胞。多核球和周邊血液單核性細胞也較易黏著於受感染的內皮細胞，並會進一步地造成細胞損傷。登革病毒的抗體也會對內皮細胞造成傷害。綜上所述，登革病毒感染引起凝血和纖維蛋白溶解系統活化的不平衡以及產生細胞素可能是造成出血之原因。

Dengue hemorrhagic fever (DHF) is an acute, potentially life-threatening, capillary leakage syndrome caused by the dengue virus (DV), a group of four antigenically related flavivirus designated serotypes 1 through 4. In contrast, classical dengue fever (DF) is an acute self-limited febrile illness. The clinical symptoms of DHF/DSS include plasma leakage documented by hemoconcentration, thrombocytopenia, and hypovolemic shock. The mechanism of DHF/DSS is still not fully understood. There are several evidences suggesting that hemorrhage in DHF is related to a combination of different factors, including thrombocytopenia, coagulopathy, and vasculopathy. In this study, the goals were aimed on the coagulopathy and vasculopathy induced by dengue virus infection, using samples from DHF/DSS and DF patients as well as an in vitro system of human endothelial cells to understand the mechanism of hemorrhage in DV infection.
The platelet count, prothombin time (PT), activated partial thromoplastin time (APTT), levels of tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) were compared in 25 dengue patients with or without hemorrhage at different time after fever onset. Thrombocytopenia was observed early in DHF/DSS patients. Prothombin time in all dengue patients was normal except in the death case. However, APTT was prolonged in patients with DHF/DSS, but not in patients with DF. In addition, a dramatic increase of tPA was found in the early stage of DHF/DSS patients but not in DF patients. In the convalescent phase, levels of PAI-1 increased while levels of tPA declined to normal range in both DHF/DSS and DF patients. The tPA/PAI-1 ratio significantly increased in the acute phase of the DHF/DSS patients, suggesting a stage of hyperfibrinolysis that may cause hemorrhage through the imbalance of fibrinolysis. The APTT and tPA/PAI-1 ratio during the first 48 h of hospitalization may serve as a predictor of DHF/DSS. In addition, DV infection of human endothelial cells also induced tPA but not PAI-1 production. The tPA production induced by dengue virus infection was IL-6 dependent. Moreover, cross-reactive antibodies present in dengue patients bound to human plasminogen and inhibited plasmin activity in vitro, and might protect plasmin from binding by the inhibitors in vivo. However, these cross-reactive antibodies enhanced plasminogen activation by urokinase.
On the other hand, the functional alterations of human umbilical cord vein endothelial cell (HUVEC) and human microvascular endothelial cell-1 (HMEC-1) after DV infection were studied. DV infection of HUVEC was confirmed by the increase of plaque forming units in the culture supernatant, replicating viral RNA, and the immunofluorescence assay. HUVEC produced large amounts of interleukin 6 (IL-6) but not IL-1b after DV infection. In addition, increase of serum levels of IL-6 was observed in dengue hemorrhage fever patients but not in dengue fever patients. DV infection did not directly cause endothelial cell damage as demonstrated by TM release and permeability change. However, DV-infected EC produced large amounts of chemokines, such as IL-8 and RANTES, which may recruit leukocytes to the local site of infection and caused damage. High levels of IL-8 and RANTES were also observed in DHF/DSS patients. PMN and PBMC preferentially adhered to DV-infected EC, and caused endothelial cells damage. Cross-reactive antibodies to dengue virus also caused damage to DV-infected EC. Taken together, the unbalanced activation of coagulation and fibrinolysis as well as the production of cytokines and chemokines may account for the development of hemorrhage after dengue virus infection.

封面
總目錄
授權書
誌謝
中文摘要
英文摘要
縮寫指引
表目錄
圖目錄
緒論
研究動機與實驗設計
材料及方法
1. 儀器
2. 登革病人臨床檢驗
3. 登革病毒感染細胞模式之建立
4. 登革病毒感染細胞之確定
5. 產生cross-reactive antibodies並測試其結合能力
6. Cross-reactive antibodies對纖溶系統功能之影響
7. 登革病毒感染對內皮細胞功能之影響
結果
A 登革病毒感染引起凝血功能缺失(coagulopathy)
1. 登革病毒感染對凝血系統(coagulation)的影響
1.1 登革出血熱(DGF/DSS)及登革熱(DF)病人體內血小板數目的變化
1.2 登革出血熱及登革熱病人凝血脢還原時間(PT)及活化部份凝血活脢時間(APTT)的變化
2. 登革病毒脢染對纖維蛋白溶解系統(fibrinolysis)的影響
2.1 登革病毒感染對組織纖溶脢活化劑(tPA)產量的影響
2.2 登革病毒感染對纖溶脢活化劑抑制劑(PAI-1)產量的影響
3. 抗登革病毒抗體對纖維蛋白溶解系統的影響
3.1 Anti-D4E及anti-plasminogen抗體之mmunogenicity
3.2 抗體對纖維蛋白溶脢(plasmin)活生的抑制
3.3 抗體對纖維蛋白溶脢原(plasminogen)活化的影響
B 登革病毒感染引起內皮細胞病變(vasculopathy)
1. 登革病毒感染內皮細胞模式之建立
2. 登革病毒感染對於內皮細胞功能的影響
2.1 登革病毒感染對內皮細胞受損的影響
2.2 登革病毒感染引白血球及產生抗體對於內皮細胞受損的影響
2.3 登革病毒感染對內皮細胞產生細胞素的影響
2. 抗體毒藥物對登革病毒感染的影響
3.1 抗病毒藥物對登革病毒複製能力的影響
3.2 抗病毒藥物對登革病毒引起之細胞素產生的影響
總結
討論
參考文獻
表附錄
圖附錄
發表之論文

lAdes, E. W., F. J. Candal, R. A. Swerlick, V. G. George, S. Summers, D. Bosse, and T. J. Lawley. HMEC-1: Establishment of an immortalized human microvascular endothelial cell line. J. Invest. Derm. 99:683-690, 1992.
lAndrews, B. S, A. N. Theofilopoulos, C. J. Peters, D. J. Loskutoff, W. E. Brandt, and F. J. Dixon. Replication of dengue and junin viruses in cultured rabbit and human endothelial cells. Infect. Immun. 20:776-781, 1978.
lAvirutnan, P., P. Malasit, B. Seliger, S. Bhakdi, and M. Husmann. Dengue virus infection of human endothelial cells leads to chemokine production, complement activation, and apoptosis. J. Immunol. 161:6338-6346, 1998.
lBancroft, T. L. On the etiology of dengue fever. Aust. Med. Gaz. 25:17-18, 1906.
lBethell, D. B., K. Flobbe, X. T. Cao, N. P. Day, T. P. Pham, W. A. Buurman, M. J. Cardosa, N. J. White, and D. Kwiatowski. Pathophysiologic and prognostic role of cytokines in dengue hemorrhagic fever. J. Infect. Dis. 177:778-782, 1998.
lBevilacqua, M. P., J. S. Pober, G. R. Majeau, W. Fiers, R. S. Cotran, and M. A. Jr. Gimbrone. Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1. Proc. Natl. Acad. Sci. USA. 4533-4537, 1986.
lBhamarapravati, N. Hemostatic defects in dengue hemorrhagic fever. Rev. Infect. Dis. 11: S826-S829, 1989.
lBierman, H. R., and E. R. Nelson. Hematodepressive virus diseases of Thailand. Ann. Intern. Med. 62:867-884, 1965.
lBonner, S. M., and M. A. O''Sullivan. Endothelial cell monolayers as a model system to investigate dengue shock syndrome. J. Virol. Methods. 71:159-167, 1998.
lCatanzaro, P. J., W. E. Brandt, W. R. Hogrefe, and P. K. Russell. Detection of dengue cell-surface antigens by peroxidase-labeled antibodies and immune cytolysis. Infect Immun 10: 381-388, 1974.
lChang, D. M., and M. F. Shaio. Production of interleukin-1 (IL-1) and IL-1 inhibitor by human monocytes exposed to dengue virus. J. Infect. Dis. 170:811-817, 1994.
lChen, Y., T. Maguire, and R. M. Marks. Demonstration of binding of dengue virus envelope protein to target cells. J. Virol. 70:8765-8772, 1996.
lChen, Y., T. Maguire, R. E. Hileman, J. R. Fromm, J. D. Esko, R. J. Linhardt, and R. M. Marks. Dengue virus infectivity depends on envelope protein binding to target cell heparan sulfate. Nature Medicine 8: 866-871, 1997.
lChungue, E., L. Poli, C. Roche, P. Gestas, P. Glaziou, and L. J. Markoff. Correlation between detection of plasminogen cross-reactive antibodies and hemorrhage in dengue virus infection. J. Infect. Dis. 170:1304-1307, 1994.
lCitarella, F., A. Felici, M. Brouwer, J. Wagstaff, A. Fantoni, and C. E. Hack. Interleukin-6 downregulates factor XII production by human hepatoma cell line (HepG2). Blood 90:1501-1507, 1997.
lCollen, D. The plasminogen (fibrinolytic) system. Thromb. Hemost. 82:259-270, 1999.
lCollen, D., and H. R. Lijnen. Basic and clinical aspects of fibrinolysis and thrombolysis. Blood 78:3114-3124, 1991.
lCosgriff, T. M. Viruses and hemostasis. Rev. Infect. Dis. 11 Suppl 4:S672-S688, 1989.
lDavie, E. W., K. Fujikawa, and W. Kisiel. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry. 30:10363-10370, 1991.
lDichek, D., and T. Quertermous. Thrombin regulation of mRNA levels of tissue plasminogen activator and plasminogen activator inhibitor-1 in cultured human umbilical vein endothelial cells. Blood 74:222-228, 1989.
lDinarello, C. A. The proinflammatory cytokines interleukin-1 and tumor necrosis factor and treatment of the septic shock syndrome. J. Infect. Dis. 163: 1177-1184, 1991.
lDuchini, A., S. Govindarajan, M. Santucci, G. Zampi, and F. M. Hofman. Effects of tumor necrosis factor-alpha and interleukin-6 on fluid-phase permeability and ammonia diffusion in CNS-derived endothelial cells. J. Invest. Med. 44: 474-482, 1996.
lDugan, L. L., D. M. Turetsky, C. Du, D. Lobner, M. Wheeler, C. R. Almli, C. K. F. Shen, T. Y. Lub, D. W. Choi, and T. S. Lin. Carboxyfullerenes as neuroprotective agents. Proc. Natl. Acad. Sci. USA. 94:9434-9439, 1997.
lDugan, L. L., J. K. Gabrielsen, S. P. Yu, T. S. Lin, and D. W. Choi. Buckminsterfullerenol free radical scavenger reduce excitotoxic and apoptotic death of cultured cortical neurons. Neurobiol. Dis. 3:129-135, 1996.
lFunahara, Y., A. Shirahata, and Sumarmo. Coagulopathy in DHF/DSS and elimination of the risk factor. ICMR Annual 5:9-15, 1985.
lFunahara, Y., Sumarmo, and R. Wirawan. Features of DIC in dengue hemorrhagic fever. Bibliotheca Haematologica 49:201-211, 1983.
lFunahara, Y., Y. Okuno, N. Fujita, S. Okamoto, K. Fukai, and T. Hotta. In vitro decrease of human platelet count due to binding of specific antibody on the dengue virus binding to the platelet. ICMR Annual 1:35-42, 1981.
lGagnon, S. J., F. A. Ennis, and A. L. Rothman. Bystander target cell lysis and cytokine production by dengue virus-specific human CD4+ cytotoxic T lymphocyte clones. J. Virol. 73:3623-3629, 1999.
lGaldiero, M., G. C. de l’Ero, and A. Marcatili. Cytokine and adhesion molecule expression in human monocytes and endothelial cells stimulated with bacterial heat shock proteins. Infect. Immun. 65: 699-707, 1997.
lGreen, S., D. W. Vaughn, S. Kanayanarooj, S. Nimmannitya, S. Suntayakorn, A. Nisalak, R. Lew, B. I. Innis, I. Kurane, A. L. Rothman, and F. A. Ennis. Early immune activation in acute dengue is related to development of plasma leakage and disease severity. J. Infect. Dis. 179:755-762, 1999.
lGubler, D. J. Dengue and dengue hemorrhagic fever. Clin. Microbio. Rev. 11:480-496, 1998.
lGubler, D. J., D. Reed, L. Rosen, and J. C. J. Hitchcock. Epidemiologic, clinical and virological observations on dengue in the Kingdom of Tonga. Am. J. Trop. Med. Hyg. 27:581-589, 1978.
lHalstead, S. B. and E. J. O’Rourke. Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody. J. Exp. Med. 146: 201-207, 1977.
lHalstead, S. B. and E. J. O''Rourke. Antibody-enhanced dengue virus infection in primate leukocytes. Nature. 265:739-741, 1977.
lHalstead, S. B. Antibody, macrophage, dengue virus infection, shock, and hemorrhage: A pathogenetic cascade. Rev. Infect. Dis. 11: S830-S839, 1989.
lHalstead, S. B. Dengue: hematologic aspects. Semin. Hematol. 19: 116-131, 1982.
lHalstead, S. B. Immunological parameters of togavirus disease syndromes, p. 107-173, In R. W. Schlesinger (ed.), The togaviruses. Academic Press, Inc., New York. 1980.
lHarn, M. R., Y. L. Chiang, M. J. Tian, Y. H. Chang, and Y. C. Ko. J. Formosan Med. Asso. 92 Sup1: S39-S43, 1993.
lHathirat, P., P. Isarangkura, T. Srichaikul, V. Suvatte, and C. Mitrakul. Abnormal hemostasis in dengue hemorrhagic fever. Southeast Asian J. Trop. Med. Pub. Hlth. 24: 80-85, 1993.
lHenchal, E. A. and J. R. Putnak. The dengue virus. Clin. Micro. Rev. 3: 376-396, 1990.
lHenkin, J., P. Marcotte, and H. Yang. The plasminogen-plasmin system. Prog. Cardiovasc. Dis. 24: 135-164, 1991.
lHober, D., A. S. Delannoy, S. Benyoucef, D. De Groote, and P. Wattre. High levels of sTNFR p75 and TNF alpha in dengue-infected patients. Microbiol. Immunol. 40:569-573, 1996.
lHober, D., L. Poli, B. Roblin, P. Gestas, E. Chungue, G. Granic, P. Imbert, J. L. Pecarere, R. Vergez-Pascal, P. Wattre, and et al.: Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta) in dengue-infected patients. Amer. J. Trop. Med. Hyg. 48:324-331, 1993.
lHosoya, S., E. Ohbayashi, K. Matsushima, H. Takeuchi, M. Yamazaki, Y. Shibata, and Y. Abiko. Stimulatory effect of interleukin-6 on plasminogen activator activity from human dental pulp cells. J. Endodontics 24:331-334, 1998.
lHuang, Y. H., B. I. Chang, H. Y. Lei, H. S. Liu, C. C. Liu, H. L. Wu, and T. M. Yeh. Antibodies against dengue virus E protein peptide bind to human plasminogen and inhibit plasmin activity. Clin. Exp. Immunol. 110:35-40, 1997.
lHumphries, S. E. Genetic regulation of fibrinogen. Eur. Heart J. 16 suppl A:16-19, 1995.
lIsarangkura, P. B., B. Pongpanich, P. Pintadit, P. Panichyakarn, and A. Valyasevi. Hemostatic derangement in dengue hemorrhagic fever. Southeast Asian J. Trop. Med. Pub. Hlth. 18:331-339, 1987.
lJenkins, G. R., D. Seiffert, R. J. Parmer, and L. A. Miles. Regulation of plasminogen gene expression by interleukin-6. Blood 89:2394-2403, 1997.
lJerushalmy, Z., and M. B. Zucker. Some effects of fibrinogen degradation products (FDP) on blood platelets. Thromb. Diath. Haemorrh. 15:413-419, 1966.
lKagitani, H., M. Tagawa, M. Hatanaka, T. Ikari, A. Saito, H. Bando, K. Okada, and O. Matsuo. Expression in E. coli of finger-domain lacking tissue plasminogen activator with high fibrin affinity. FEBS Lett. 189:145-149, 1985.
lKaiser, L. and H. V. Jr. Sparks. Endothelial cells: not just a ceilophone wrapper. Arch. Intern. Med. 147: 569-573, 1987.
lKey, N. S., G. M. Vercellotti, J. C. Winkelemann, C. F. Moldow, J. L. Goodman, N. L. Esmon, C. T. Esmon, and H. S. Jacob. Infection of vascular endothelial cells with herpes simplex virus enhances tissue factor activity and reduces thrombomodulin expression. Proc. Natl. Acad. Sci. USA. 87:7095-7097, 1990.
lKey, N. S., R. R. Bach, G. M. Vercellotti, and C. F. Moldow. Herpes simplex virus type 1 does not require productive infection to induce tissue factor in human umbilical vein endothelial cells. Lab. Invest. 68:645-651, 1993.
lKillen, H. and M. A. O''Sullivan. Detection of dengue virus by in situ hybridization. J. Virol. Methods. 41:135-146, 1993.
lKo, Y. C. Epidemiology of dengue fever in Taiwan. Kaohsiung J. Med. Sci. 5:1-11, 1989.
lKoff, W. C., J. L. Jr. Elm, and S. B. Halstead. Antiviral effects of ribavirin and 6-mercapto-9-tetrahydro-2-furylpurine against dengue viruses in vitro. Antiviral Res 2: 69-79, 1982.
lKooistra, T., J. van der Berg, and A. Tons. Protein kinase C and the stimulation of tissue plasminogen activator synthesis in cultured human endothelial cells. Biochem. J. 247:605-612, 1987.
lKrishnaswamy, G., J. Kelly, L. Yerra, J. K. Smith, and D. S. Chi. Human endothelium as a source of multifunctional cytokines: molecular regulation and possible role in human disease. J. Interferon Cytokine Res. 19: 91-104, 1999.
lKurane I., B. L. Innis, A. Nisalak, C. Hoke, S. Nimmannitya, A. Meager, and F. A. Ennis. Human T cell responses to dengue virus antigens. Proliferative responses and interferon gamma production. J. Clin. Invest. 83:506-513, 1989.
lKurane, I., and F. A. Ennis. Immunopathogenesis of dengue infections, p. 273-290. In D. J. Gubler and G. Kuno (ed.), Dengue and dengue hemorrhagic fever. CAB International, London, United Kingdom. 1997.
lKurane, I., B. L. Innis, S. Nimmannitya, A. Nisalak, A. Meager, J. Janus, and F. A. Ennis. Activation of T lymphocytes in dengue virus infections. High levels of soluble interleukin 2 receptor, soluble CD4, soluble CD8, interleukin 2, and interferon gamma in sera of children with dengue. J. Clin. Invest. 88:1473-1480, 1991.
lLevin, E. G., K. Marotti, and L. Santell. Protein kinase C and the stimulation of tissue plasminogen activator release form human endothelial cells. Dependence on the elevation of messanger RNA. J. Biol. Chem. 264:16030-16036,1989.
lLiu, W. T., C. L. Chen, S. S. Lee, C. C. Chan, F. L. Lo, and Y. C. Ko. Isolation of dengue virus with a human promonocyte cell line. Amer. J. Trop. Med. Hyg. 44:494-499, 1991.
lMacGregor, R. R., H. M. Friedman, E. J. Macarak, and N. A. Kefalides. Virus infection of endothelial cells increases granulocyte adherence. J. Clin. Invest. 65:1469-1477, 1980.
lMalasit P. Complement and dengue hemorrhagic fever/shock syndrome. Southeast Asian J. Med. Public Hlth 18:316-320, 1987.
lMalinoski, F. J., S. E. Hasty, M. A. Ussery, and J. M. Dalrymple. Prophylactic ribavirin treatment of dengue type 1 infection in rhesus monkeys. Antiviral Res 13:139-149, 1990.
lMann, K. G. Biochemistry and physiology of blood coagulation. Thromb. Haemost. 82:165-174, 1999.
lMantovani, A., F. Bussolino, and E. Dejana. Cytokine regulation of endothelial cell function. FASEB J. 6:2591-2599, 1992.
lMarkoff, L. J., B. L. Innis, R. Houghten, and L. S. Henchal. Development of cross-reactive antibodies to plasminogen during the immune response to dengue virus infection. J. Infect. Dis. 164:294-301, 1991.
lMason, P. W. Maturation of Japanese encephalitis virus glycoproteins produced by infected mammalian and mosquito cells. Virology 169:354-364, 1989.
lMcKay, D. G. and W. Margaretten. Disseminated intravascular coagulation in virus diseases. Arch. Intern. Med. 120:129-152, 1967.
lMedcalf, R. L., and W. D. Schleuning. Regulation of human tissue-type plasminogen activator gene transcription by epidermal growth factor and cAMP. Mol. Endocrinol. 5: 1773-1779, 1991.
lMedcalf, R. L., E. Van den Berg, and W. D. Schleuning. Glucocorticoid modulated gene expression of tissue and urinary-type plasminogen activator and plasminogen activator inhibitor 1 and 2. J. Cell. Biol. 106: 971-978, 1988.
lMitrakul, C. Bleeding problem in dengue haemorrhagic fever: platelets and coagulation changes. Southeast Asian J. Trop. Med. Pub. Hlth. 18:407-412, 1987.
lMitrakul, C., M. Poshyachinda, P. Futrakul, N. Sangkawibha, and S. Ahandrik. Hemostatic and platelet kinetic studies in dengue hemorrhagic fever. Am. J. Trop. Med. Hyg. 26:975-984, 1977.
lNawroth, P. P., D. A. Handley, C. T. Esmon, and D. M. Stern. Interleukin 1 induces endothelial cell procoagulant while suppressing cell-surface anti-coagulant activity. Proc. Natl. Acad. Sci. USA. 83: 3460-3464, 1986.
lNg, M. L., and L. C. Corner. Detection of some dengue-2 virus antigens in infected cells using immuno-microscopy. Arch Virol 140:197-208, 1989.
lNicholson, A. C., and D. P. Hajjar. Viral activation of the coagulation cascade. Am. Heart J. 138:S461-S464, 1991.
lNimmannitya, S. Clinical spectrum and management of dengue haemorrhagic fever. Southeast Asian J. Trop. Med. Pub. Hlth. 18:392-397, 1987.
lPereira, S. P., P. G. Langley, and R. Willians. The management of abnormalities of hemostasis in acute liver failure. Semin. Liver Dis. 16: 403-414, 1996.
lPober, J., and R. S. Cotran. Cytokines and endothelial cell biology. Physiol. Rev. 70:427-451, 1990.
lRaghupathy, R., U. C. Chaturvedi, H. Al-Sayer, E. A. Elbishbishi, R. Agarwal, R. Nagar, S. Kapoor, A. Misra, A. Mathur, H. Nusrat, F. Azizieh, M. A. Y. Khan, and A. S. Mustafa. Elevated levels of IL-8 in dengue hemorrhagic fever. J. Med. Virol. 56:280-285, 1998.
lRice, C. M., E. M. Lenches, S. R. Eddy, S. J. Shin, R. L. Sheets, and J. H. Strauss. Nucleotide sequence of yellow fever virus: implications for flavivirus gene expression and evolution. Science 229:726-733, 1985.
lRomano, M., M. Sironi, C. Toniatti, N. Polentarutti, P. Fruscella, P. Ghezzi, R. Faggioni, W. Luini, V. van Hinsbergh, S. Sozzani, F. Bussolino, V. Poli, G. Ciliberto, and A. Mantovani. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 6:315-325, 1997.
lRosen, L. The Emperor’s new clothes revisited, or reflections on the pathogenesis of dengue hemorrhagic fever. Am. J. Trop. Med. Hyg. 26:337-343, 1977.
lRothman, A. L. Viral pathogenesis of dengue infections, p. 245-272. In D. J. Gubler and G. Kuno (ed.), Dengue and dengue hemorrhagic fever. CAB International, London, United Kingdom. 1997.
lRothman, A. L., and F. A. Ennis. Immunopathogenesis of dengue hemorrhagic fever. Virol. 257:1-6, 1999.
lRox, J. M., J. Reinartz, and M. D. Kramer. Interleukin-1 beta upregulates tissue-type plsminogen activator in a keratinocyte cell line (HaCaT). Arch. Dermatol. Res. 288:554-558, 1996.
lRuf, W. and B. M. Mueller. Tissue factor signaling. Thromb. Haemost. 82:175-182, 1999.
lRussell, P. K., W. E. Brandt, and J. M. Darlymple. Chemical and antigenic structure of flaviviruses, p. 503-529. In R. W. Schlesinger (ed.) The togaviruses. Academic Press, Inc., New York. 1980.
lSabin, A. B. Dengue, p. 361-373. In T. Rivers and F. Horsfall (ed.) Viral and rickettidal infections of man. J. B. Lippinocott., Philadelphia. 1959.
lSahaphong, S., S. Riengrojpitak, N. Bhamarapravati, and T. Chirachariyavej. Electron microscopic study of the vascular endothelial cell in dengue hemorrhagic fever. Southeast Asian J. Med. Public Hlth. 11:194-204, 1980.
lSatoh, M., K. Matsuo, H. Kiriya, T. Mashino, M. Hirobe, and I. Takayanagi. Inhibitory effect of a fullerene derivative, monomalonic acid C60, on nitric oxide-dependent relaxation of arotic smooth muscle. Gen. Pharmacol. 29:345-351, 1997.
lSchleef, R. R., M. P. Bevilacqua, M. Sawdey, M. A. Jr. Gimbrone, and D. J. Loskutoff. Cytokine activation of vascular endothelium. Effects on tissue-type plasminogen activator and type 1 plasminogen activator inhibitor. J. Biol. Chem. 263: 5797-5803, 1988.
lShi, G. Y., B. I. Chang, S. M. Chen, D. H. Wu, and H. L. Wu. Function of streptokinase fragments in plasminogen activation. Biochem. J. 304:235-241, 1994.
lSim, P. S., D. R. H. Fayle, W. F. Doe, and R. W. Stephens. Monoclonal antibodies inhibitory to human plasmin: definitive demonstration of a role of plasmin in activating the proenzyme of urokinase-type plasminogen activator. Eur J Biochem 158:537-542, 1986.
lSimmons, J. S., J. H. St. John, and F. H. K. Reynolds. Experimental studies of dengue. Philipp. J. Sci. 44:1-247, 1931.
lSrichaikul, T. Disseminated intravascular coagulation in dengue haemorrhagic fever. Southeast Asian J. Med. Public Hlth. 18:303-311, 1987.
lSteven, M. L. Hemostasis, in: Fundamentals of clinical hematology, Huffard, L., C. Martine, J. K. Semak, T. B. Wiggers, and K. N. Zell, eds. W. B. Saunders Publishers, Pennsylvania, 1997: 227-257.
lStouthard, J. M. L., M. Levi, E. Hack, C. H. N. Veenhof, H. A. Romijn, H. P. Sauerwein, and T. van der Poll. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb. Haemostasis 76:738-742, 1996.
lSuvatte, V. D. Pongpipat, S. Tuchinda, A. Ratanawongs, P. Tuchinda, and S. Bukkavesa. Studies on serum complement C3 and fibrin degradation product in Thai hemorrhagic fever. J. Med. Asso. Thailand 56:24-32, 1973.
lSuvatte, V. Dengue hemorrhagic fever: Hematological abnormalities and pathogenesis. J. Med. Ass. Thailand 61:53-58, 1978.
lTakashima, H., K. Eguchi, A. Kawakami, Y. Kawabe, K. Migita, M. Sakai, T. Origuchi, and S. Nagataki. Cytokine production by endothelial cells infected with human T cell lymphotropic virus type 1. Ann. Rheum. Dis. 55: 632-637, 1996.
lThein, S., M. M. Aung, T. N. Shwe, M. Aye, A. Zaw, K. Aye, K. M. Aye, and J. Aaskov. Risk factors in dengue shock syndrome. Am. J. Trop. Med. Hyg. 56:169-182, 1997.
lVan Gorp, E. C. M., and H. ten Cate. Coagulation monitoring. In: Webb, A. R., M. J. Shapiro, M. Singer, and P. M. Suter, eds. Oxford textbook of critical care medicine. Oxford, UK: Oxford University Press, 1999:1170-1173.
lvan Hinsbergh, V. W., K. A. Bauer, T. Kooistra, C. Kluft, G. Dooijewaard, M. L. Sherman, and W. Nieuwenhuizen. Progress of fibrinolysis during tumor necrosis factor infusions in humans. Concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products. Blood 76:2284-2289, 1990.
lVitarana, T., H. de Silva, N. Withana, and C. Gunasekera. Elevated tumour necrosis factor in dengue fever and dengue haemorrhagic fever. Ceylon Med. J. 36: 63-65, 1991.
lWilson, H. M., N. E. Haites, and N. A. Booth. Opposing effects of interleukin-1 and transforming growth factor-beta on the regulation of tissue-type plasminogen activator and plasminogen activator inhibitor type-1 expression by human mesangial cells. Exp. Nephrol. 5:233-238, 1997.
lWilson, H. M., N. E. Haites, F. J. Reid, and N. A. Booth. Interleukin-1 beta up-regulates the plasminogen activator/plasmin system in human mesangial cells. Kidney Int. 49: 1097-1104, 1996.
lWiman B. Primary structure of the B-chain of human plasmin. Eur. J. Biochem. 76: 159-65, 1977.
lWorld Health Organization. Pathogenetic mechanisms in dengue hemorrhagic fever: report of an international collaborative study. Bull WHO 48:117-133, 1973.
lWorld Health Organization. Technical guides and diagnosis, treatment, surveillance, prevention and control of dengue hemorrhagic fever. World Health Organization, Geneva. 1975.
lWu, H. L., G. Y. Shi, and M. L. Bender. Preparation and purification of microplasmin. Proc. Natl. Acad. Sci. USA 84:8292-8295, 1987.
lWu, Y. C. Epidemic dengue 2 on Liouchyou Shiang, Pingtung County in 1981. Chinese J. Microbiol. Immunol. 19:203-211, 1986.
lYang, K. D., C. L. Wang, and M. F. Shaio. Production of cytokines and platelet activating factor in secondary virus infections. J. Infect. Dis. 172: 604-605, 1995.
lYu, H. S., M. T. Wang, C. L. Tai, S. A. Yang, and C. H. Chien. Skin eruption and histopathological changes in dengue fever. Kaohsiung J. Med. Sci. 5:17-23, 1989.