Cross-reactivity of human molecular markers for detection of prethrombotic states in various animal species

Ravanat, Catherine; Freund, Monique; Dol, Frédérique; Cadroy, Yves; Roussi, J; Incardona, Francesca; Maffrand, J.P.; Boneu, B; Drouet, L.; Legrand, Chantal; Jm, Herbert; Cazenave, J.-P.

doi:10.1097/00001721-199507000-00012

Cited by 83 publications

(51 citation statements)

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“…Blood was collected in 3.8% sodium citrate (9:1 vol/vol) and centrifuged at 4,000 g for 5 min, and the supernatant was further centrifuged at 12,000 g for 10 min and stored at Ϫ70°C. TAT complex was analyzed with an ELISA kit (Enzygnost TAT micro, Dade Behring), which detects thrombin generation in rat plasma (20).…”

Section: Methodsmentioning

confidence: 99%

Antithrombotic activity of kininogen is mediated by inhibitory effects of domain 3 during arterial injury in vivo

Hassan

Sáinz

Khan

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Hassan S, Sainz IM, Khan MM, Bradford HN, Isordia-Salas I, Kashem SW, Sartor RB, Colman RW. Antithrombotic activity of kininogen is mediated by inhibitory effects of domain 3 during arterial injury in vivo. Am J Physiol Heart Circ Physiol 292: H2959 -H2965, 2007. First published February 9, 2007 doi:10.1152/ajpheart.00730.2006.-High-molecular-weight kininogen (HK) and its domain 3 (D3) exhibit anticoagulant properties and inhibit platelet activation at low thrombin concentration in vitro. We hypothesized that the rapid occlusive thrombosis in HK-deficient (HKd) rats following endothelial injury of the aorta results from enhanced platelet aggregation by thrombin. The effects of D3 (G235-M357) or D3-derived peptides on thrombosis in vivo were tested. D3 and its exon 7C terminal peptide (E7CP, K270-Q292), expressed as glutathione S-transferase (GST) fusion proteins (GST-D3, GST-E7CP), or GST alone, as well as cleaved HK (HKa) or synthetic peptide E7CP, were infused intravenously 10 min before endothelial injury. Blood flow was reduced down to 10% of baseline flow within 28 Ϯ 5.2 min by a platelet-fibrin thrombus in GST-treated HKd rats compared with Ͼ240 min in GST-treated normal HK rats (wild type). GST-D3, GST-E7CP, HKa, or E7CP infusion prolonged the flow time to 233, Ͼ240, 223, and Ͼ240 min, respectively, in HKd rats. When GST-E7CP was infused 10 min after the injury, blood flow was maintained for Ͼ240 min. Thrombin-antithrombin concentrations were elevated by injury in HKd rats receiving GST from 35 to 55 g/l and decreased with GST-E7CP, HKa, or E7CP reconstitution to 40, 15, and 9 g/l, respectively. We conclude that HKd rats are prothrombotic and that HKa, kininogen D3, and its fragment E7CP modulate arterial thrombosis after endothelial injury. arterial thrombosis; endothelial injury; kininogen-deficient rat HIGH-MOLECULAR-WEIGHT KININOGEN (HK) and low-molecularweight kininogen (LK) are multifunctional plasma proteins that are substrates for plasma kallikrein and tissue kallikrein yielding bradykinin and kallidin, respectively. The remaining cleaved HK (HKa), lacking bradykinin, exhibits antiadhesive (26) and antiangiogenic (5) activity as well as enhancing cell-associated fibrinolysis (6) and releasing cytokines and chemokines to enhance inflammation (15). Although deficiency of HK results in vitro in a prolonged activated partial thromboplastin time, patients with plasma HK deficiency do not have a hemorrhagic diathesis (4). Whether individuals with total kininogen deficiency are thrombophilic has not been determined because of the rarity of the disorder. However, both kininogens bind to platelets (9,19,25) and selectively inhibit the high-affinity thrombin binding to platelet glycoprotein (GP)Ib (14, 16). Therefore, animal models are the only modality currently available to resolve this issue.Kininogens are proteins composed of multiple domains (Fig. 1A), each with associated functional activities. The heavy chain, domain (D)1-D3, and bradykinin contained in D4 are common to both HK and LK, while the lig...

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Section: Methodsmentioning

confidence: 99%

Antithrombotic activity of kininogen is mediated by inhibitory effects of domain 3 during arterial injury in vivo

Hassan

Sáinz

Khan

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…The first drop of blood was discarded. The TAT ELISA (Enzygnost TAT, Newark, Delaware, USA) was used according to manufacturer's instructions and has been validated for determination of TAT levels in mice (24).…”

Section: Methodsmentioning

confidence: 99%

Novel therapeutic approach for hemophilia using gene delivery of an engineered secreted activated Factor VII

Margaritis¹,

Arruda²,

Aljamali³

et al. 2004

J. Clin. Invest.

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Hemophilia is a bleeding disorder caused by mutations in the genes encoding coagulation Factor VIII (FVIII) or FIX. Current treatment is through intravenous infusion of the missing protein. The major complication of treatment is the development of neutralizing Ab’s to the clotting factor. Infusion of recombinant activated human Factor VII (rhFVIIa), driving procoagulant reactions independently of human FVIII (hFVIII) or hFIX, has been successful in such patients and could in theory provide hemostasis in all hemophilia patients. However, its high cost and short half-life have limited its use. Here, we report a novel treatment strategy with a recombinant adeno-associated virus vector delivering a modified FVII transgene that can be intracellularly processed and secreted as activated FVII (FVIIa). We show long-term expression, as well as phenotypic correction of hemophilia B mice following gene transfer of the murine FVIIa homolog, with no evidence of thrombotic complications at these doses. These data hold promise for a potential treatment for hemophilia and other bleeding disorders

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“…Blood samples for other assays were obtained from the inferior vena cava of anticoagulated mice (8,000 U heparin intraperitoneally, unfractionated porcine heparin, sodium-salt; Life Technologies Inc., Grand Island, New York, USA). Thrombinantithrombin complexes (TAT) and D-Dimer were determined using commercially available ELISA systems that recognized mouse TAT (23) and mouse D-Dimer (24), respectively (Enzygnost TAT micro; Behring Diagnostic Inc., Westwood, Massachusetts, USA, and Asserachrom D-Di; American Bioproducts Co., Parsippany, New Jersey, USA, respectively). Fibrinogen levels were measured by sandwich ELISA using a rabbit anti-human fibrinogen antibody (DAKO Corp., Carpinteria, California, USA) and a peroxidase-conjugated goat anti-mouse fibrinogen antibody (Accurate International, Westbury, New York, USA).…”

Section: Methodsmentioning

confidence: 99%

Endothelium-specific loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis

et al. 2001

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The thrombomodulin (TM) gene was ablated in mice in a cell type-restricted manner from vascular endothelium by Cre-recombinase-mediated excision controlled by the endothelial cell lineage-specific Tie2 promoter. Forty percent of mutant (TMLox-) mice display a distinct lethal embryonic phenotype not observed in completely TM-deficient embryos. The remaining 60% of TMLox mice survive beyond birth, but invariably succumb to a severe hypercoagulable state and massive thrombosis after 3 weeks, terminating in a lethal consumptive coagulopathy. The progression of thrombosis was age-and sex-dependent. Disruption of the TM/protein C pathway was not associated with a latent proinflammatory state. Disease onset and progression could be prevented by warfarin anticoagulation. These results show that in mice, loss of endothelial cell TM function causes spontaneous and fatal thrombosis in the arterial and venous circulation, resulting from unfettered activation of the coagulation system. The combination of complete disease penetrance, uniform disease onset at young age, large vessel thrombosis of the extremities and multiple organ systems, and consumptive coagulopathy as the disease end-point provides a unique mouse model of human thrombotic disease.

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Cross-reactivity of human molecular markers for detection of prethrombotic states in various animal species

Cited by 83 publications

References 0 publications

Antithrombotic activity of kininogen is mediated by inhibitory effects of domain 3 during arterial injury in vivo

Antithrombotic activity of kininogen is mediated by inhibitory effects of domain 3 during arterial injury in vivo

Novel therapeutic approach for hemophilia using gene delivery of an engineered secreted activated Factor VII

Endothelium-specific loss of murine thrombomodulin disrupts the protein C anticoagulant pathway and causes juvenile-onset thrombosis

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