The Regulation of the Activaton of the Fibrinolysis System

Takada, Akikazu; Urano, Tetsumei; Takada, Yumiko

doi:10.1007/978-1-4615-3806-6_21

Cited by 2 publications

(1 citation statement)

References 61 publications

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“…When the balance between procoagulant and anticoagulant processes is disturbed, the resulting hypocoagulable or hypercoagulable states can manifest as abnormal bleeding or thromboembolic disease that complicate any preexisting conditions (Brummel-Ziedins et al 2009). The fibrinolytic pathway maintains blood fluidity by initiating the conversion of plasminogen to plasmin which in turn degrades fibrin (Takada, Urano, and Takada 1990). The primary action of the fibrinolytic system is to restore blood flow in occluded vessels (Collen 1980; Erickson et al 1985).…”

Section: Introductionmentioning

confidence: 99%

Current Practices in Preclinical Drug Development

et al. 2012

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The Health and Environmental Sciences Institute Cardiac Biomarkers Working Group surveyed the pharmaceutical development community to investigate practices in assessing hemostasis, including detection of hypocoagulable and hypercoagulable states. Scientists involved in discovery, preclinical, and clinical research were queried on laboratory evaluation of endothelium, platelets, coagulation, and fibrinolysis during safety assessment studies. Results indicated that laboratory assessment of hemostasis is inconsistent among institutions and not harmonized between preclinical and clinical studies. Hemostasis testing in preclinical drug safety studies primarily focuses on the risk of bleeding, whereas the clinical complication of thrombosis is seldom assessed. Our results reveal the need for broader utilization of biomarkers to detect altered hemostasis (e.g., endothelial and platelet activation) to improve preclinical safety assessments early in the drug development process. Survey respondents indicated a critical lack of validated markers of hypercoagulability and subclinical thrombosis in animal testing. Additional obstacles included limited blood volume, lack of cross-reacting antibodies for hemostasis testing in laboratory species, restricted availability of specialized hemostasis analyzers, and few centers of expertise in animal hemostasis testing. Establishment of translatable biomarkers of prothrombotic states in multiple species and strategic implementation of testing on an industry-wide basis are needed to better avert untoward drug complications in patient populations.

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Section: Introductionmentioning

confidence: 99%

Current Practices in Preclinical Drug Development

et al. 2012

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Chronic pulmonary hypertension‐the monocrotaline model and involvement of the hemostatic system

Schultze

Roth

1998

Journal of Toxicology and Environmental Health, Part B

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Monocrotaline (MCT) is a toxic pyrrolizidine alkaloid of plant origin. Administration of small doses of MCT or its active metabolite, monocrotaline pyrrole (MCTP), to rats causes delayed and progressive lung injury characterized by pulmonary vascular remodeling, pulmonary hypertension, and compensatory right heart hypertrophy. The lesions induced by MCT(P) administration in rats are similar to those observed in certain chronic pulmonary vascular diseases of people. This review begins with a synopsis of the hemostatic system, emphasizing the role of endothelium since endothelial cell dysfunction likely underlies the pathogenesis of MCT(P)-induced pneumotoxicity. MCT toxicology is discussed, focusing on morphologic, pulmonary mechanical, hemodynamic, and biochemical and molecular alterations that occur after toxicant exposure. Fibrin and platelet thrombosis of the pulmonary microvasculature occurs after administration of MCT(P) to rats, and several investigators have hypothesized that thrombi contribute to the lung injury and pulmonary hypertension. The evidence for involvement of the various components of the hemostatic system in MCT(P)-induced vascular injury and remodeling is reviewed. Current evidence is consistent with involvement of platelets and an altered fibrinolytic system, yet much remains to be learned about specific events and signals in the vascular pathogenesis.

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The Regulation of the Activaton of the Fibrinolysis System

Cited by 2 publications

References 61 publications

Current Practices in Preclinical Drug Development

Current Practices in Preclinical Drug Development

Chronic pulmonary hypertension‐the monocrotaline model and involvement of the hemostatic system

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