Thromb Haemostasis
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Blood coagulation factor XIII (FXIII) promotes cross-linking of fibrin during blood coagulation; impaired clot stabilization in human genetic deficiency is associated with marked pathologies of major clinical impact, including bleeding symptoms and deficient wound healing. To investigate the role of FXIII we employed homologous recombination to generate a targeted deletion of the inferred exon 7 of the FXIII-A gene. FXIII transglutaminase activity in plasma was reduced to about 50% in mice heterozygous for the mutant allele, and was abolished in homozygous null mice. ⋯ Arrest of tail-tip bleeding in FXIII-A deficient mice was markedly and significantly delayed; replacement of mutant mice with human plasma FXIII (Fibrogammin P) restored bleeding time to within the normal range. Thrombelastography (TEG) experiments demonstrated impaired clot stabilization in FXIII-A mutant mice, replacement with human FXIII led to dose-dependent TEG normalization. The mutant mice thus reiterate some key features of the human genetic disorder: they will be valuable in assessing the role of FXIII in other associated pathologies and the development of new therapies.
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We have recently shown that intravenous immunoglobulin (IVIG) therapy leads to an increased rate of anti-platelet antibody clearance in an animal model of immune thrombocytopenia. The present study was performed to confirm the importance of the FcRn receptor in mediating this effect of IVIG. ⋯ In mice lacking expression of FcRn, IVIG treatment did not increase 7E3 clearance (61.0 +/- 3.6 ml/d/kg vs. 71.5 +/- 4.0 ml/d/kg in controls). Thus, these data support the hypothesis that IVIG increases antibody elimination via saturation of FcRn.
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Plasminogen knock-out (PG(-/-)) mice provide an unique opportunity for the study of alternative mediators of fibrinolysis. Polymorpho-nuclear leucocytes (PMNs) contain non-plasmin fibrinolytic proteases, however the degree to which these cells contribute to fibrin(ogen) degradation in these animals is not known. Thrombi were generated in carotid arteries and jugular veins of PG(-/-) and wild type (PG(+/+)) mice following adventitial application of a 20% ferric chloride solution. ⋯ Furthermore, autoradiographic analysis of the I(125)-labeled fibrinogen degradation products showed the cleavage pattern by PG(-/-) PMNs to be distinct from that produced by PG(+/+) PMNs. These data suggest that a relatively greater role for PMNs-initiated fibrinolysis exists in the setting of plasminogen deficiency, although this prominence only becomes evident more than 24 h after the thrombotic insult. In addition, mechanisms responsible for the process in PG(-/-) mice may be distinct from those primarily responsible for the process in PMNs from PG(+/+) mice.
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Comparative Study
Induction of vasoactive substances differs in LPS-induced and TF-induced DIC models in rats.
We have investigated the role of two vasoactive substances, nitric oxide (NO)and endothelin (ET), in the pathophysiology of disseminated intravascular coagulation (DIC), using two types of DIC models. Experimental DIC was induced by sustained infusion of 0.1, 1, 10, or 50 mg/kg lipopolysaccharide (LPS), or 3.75 U/kg thromboplastin (TF), for 4 h via the rat tail vein. Plasma levels of both NOX (metabolites of NO) and ET were significantly increased following infusion of 0.1 mg/kg or greater of LPS in the LPS-induced DIC rat model. ⋯ Vasoconstriction, as well as depressed fibrinolytic activity, may be additional factors leading to severe organ dysfunction in the LPS-induced DIC rat model. Moreover, vasodilatation, as well as enhanced fibrinolytic activity, may help to prevent rats from severe organ dysfunction in the TF-induced DIC model. Our results suggest that modulator of vasoactive substances should be examined in the treatment of DIC.
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Systemic activation of coagulation leading to disseminated intra-vascular coagulation (DIC) is an important feature in patients with severe sepsis. Tissue factor has been shown to play a primary role in this pathological response, as revealed by the use of specific inhibitors and antagonists of the tissue factor/factor VIIa pathway. This class of agents has been demonstrated to attenuate the coagulation response in human volunteers with induced low-grade endotoxemia and to reduce mortality in primate models of Gram-negative sepsis. ⋯ In contrast to the effect of rNAPc2 on thrombin generation, there was no effect of this inhibitor on the well known enhanced systemic fibrinolytic response induced by endotoxin. In conclusion, the recombinant peptide rNAPc2 is an effective inhibitor of tissue factor-driven thrombin generation during low grade endotoxemia. These results suggest that rNAPc2 may be a promising therapeutic option to inhibit coagulation activation in patients with sepsis.