Author Correction: ADAMTS-13 regulates neutrophil recruitment in a mouse model of invasive pulmonary aspergillosis.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

ADAMTS-13 regulates neutrophil recruitment in a mouse model of invasive pulmonary aspergillosis.

Von Willebrand factor (VWF) is secreted as an acute phase protein during inflammation. ADAMTS-13 regulates the size and prothrombotic activity of VWF by it's specific proteolytic activity. To determine the relevance of this regulatory pathway for the innate inflammatory response by polymorphonuclear neutrophils (PMN), we employed a mouse model of invasive pulmonary aspergillosis (IPA) where PMN functionality is crucial for fungal clearance and survival.

Plasminogen Tochigi mice exhibit phenotypes similar to wild-type mice under experimental thrombotic conditions.

Plasminogen (Plg) is a precursor of plasmin that degrades fibrin. A race-specific A620T mutation in Plg, also known as Plg-Tochigi, originally identified in a patient with recurrent venous thromboembolism, causes dysplasminogenemia with reduced plasmin activity. The Plg-A620T mutation is present in 3-4% of individuals in East Asian populations, and as many as 50,000 Japanese are estimated to be homozygous for the mutant 620T allele.

Thrombophilia in East Asian countries: are there any genetic differences in these countries?

In recent years, genetic analyses of congenital deficiencies of three anticoagulant proteins, antithrombin, protein C (PC) and protein S (PS), in East Asian patients with venous thromboembolism (VTE) have greatly increased. The PS-K196E mutation is often identified in the Japanese population with an allelic frequency of 0.86 %, and a total of approximately 10,000 Japanese are estimated to be homozygotes.

Human CalDAG-GEFI deficiency increases bleeding and delays αIIbβ3 activation.

Affinity regulation of integrin αIIbβ3 for fibrinogen by inside-out signaling plays a critical role in hemostasis. Calcium and diacylglycerol (DAG)-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) was identified as a Rap1-activating molecule, and its role in inside-out αIIbβ3 activation was established in CalDAG-GEFI-deficient mice. However, little information regarding CalDAG-GEFI in human platelets is available.

Exacerbated venous thromboembolism in mice carrying a protein S K196E mutation.

Protein S (PS) acts as an anticoagulant cofactor for activated protein C in regulation of blood coagulation. The K196E mutation in PS is a race-specific genetic risk factor for venous thromboembolism with a prevalence of ∼2% within the Japanese population. To evaluate the thrombosis risk of the PS-K196E mutation, we generated PS-K196E knockin mice and heterozygous PS-deficient mice.

ADAMTS13 gene deletion enhances plasma high-mobility group box1 elevation and neuroinflammation in brain ischemia-reperfusion injury.

Highly adhesive glycoprotein von Willebrand factor (VWF) multimer induces platelet aggregation and leukocyte tethering or extravasation on the injured vascular wall, contributing to microvascular plugging and inflammation in brain ischemia-reperfusion. A disintegrin and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) cleaves the VWF multimer strand and reduces its prothrombotic and proinflammatory functions. Although ADAMTS13 deficiency is known to amplify post-ischemic cerebral hypoperfusion, there is no report available on the effect of ADAMTS13 on inflammation after brain ischemia.

In vivo imaging analysis of the interaction between unusually large von Willebrand factor multimers and platelets on the surface of vascular wall.

To elucidate how unusually large von Willebrand factor (UL-VWF) multimers facilitate thrombus formation, their behavior was analyzed together with that of platelets in living mice deficient in the gene encoding the protease that cleaves UL-VWF, a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13-/-). By crossing ADAMTS13-/- mice with green fluorescent protein-expressing transgenic mice (GFP mice), GFP-ADAMTS13-/- mice were obtained. The dynamics of GFP-expressing platelets were monitored employing intravital confocal fluorescent microscopy.

Impact of RGS2 deficiency on the therapeutic effect of telmisartan in angiotensin II-induced aortic aneurysm.

Regulator of G-protein signaling 2 (RGS2) negatively regulates the signaling of G-protein-coupled receptors, such as the angiotensin II (AngII) type 1 receptor by accelerating the inactivation of Gαq. Rgs2-deficient mice show increased sensitivity and prolonged responsiveness to vasoconstrictors, and genetic variations in the RGS2 gene are associated with hypertension in humans. This study aimed to clarify whether Rgs2 deficiency contributes to the development of vascular remodeling and therapeutic efficacy of the angiotensin receptor blocker telmisartan on atherosclerotic vascular damage.

The function of ADAMTS13 in thrombogenesis in vivo: insights from mutant mice.

Recently, two independent groups have established ADAMTS13-deficient mice using gene-targeting techniques. In humans, genetic or acquired deficiency in ADAMTS13 leads to a potentially fatal syndrome, thrombotic thrombocytopenic purpura (TTP). Surprisingly, ADAMTS13-deficient mice are viable with no apparent signs of TTP.

ADAMTS13 gene deletion aggravates ischemic brain damage: a possible neuroprotective role of ADAMTS13 by ameliorating postischemic hypoperfusion.

Reperfusion after brain ischemia causes thrombus formation and microcirculatory disturbances, which are dependent on the platelet glycoprotein Ib-von Willebrand factor (VWF) axis. Because ADAMTS13 cleaves VWF and limits platelet-dependent thrombus growth, ADAMTS13 may ameliorate ischemic brain damage in acute stroke. We investigated the effects of ADAMTS13 on ischemia-reperfusion injury using a 30-minute middle cerebral artery occlusion model in Adamts13(-/-) and wild-type mice.

The distal carboxyl-terminal domains of ADAMTS13 are required for regulation of in vivo thrombus formation.

ADAMTS13 is a multidomain protease that limits platelet thrombogenesis through the cleavage of von Willebrand factor (VWF). We previously identified 2 types of mouse Adamts13 gene: the 129/Sv-strain Adamts13 gene encodes the long-form ADAMTS13 having the same domains as human ADAMTS13, whereas the C57BL/6-strain Adamts13 gene encodes the short-form ADAMTS13 lacking the distal C-terminal domains. To assess the physiologic significance of the distal C-terminal domains of ADAMTS13, we generated and analyzed 129/Sv-genetic background congenic mice (Adamts13(S/S)) that carry the short-form ADAMTS13.

ADAMTS13 assays and ADAMTS13-deficient mice.

Purpose Of Review: Thrombotic thrombocytopenic purpura can be induced by acquired or congenital deficiency of the plasma von Willebrand factor-cleaving protease, ADAMTS13. Measurement of ADAMTS13 activity is important for the diagnosis and treatment of microangiopathies including thrombotic thrombocytopenic purpura. Phenotypic analysis of mice lacking the Adamts13 gene is valuable for understanding the pathogenesis of microangiopathies.

Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura.

ADAMTS13 is a plasma metalloproteinase that regulates platelet adhesion and aggregation through cleavage of von Willebrand factor (VWF) multimers. In humans, genetic or acquired deficiency in ADAMTS13 causes thrombotic thrombocytopenic purpura (TTP), a condition characterized by thrombocytopenia and hemolytic anemia with microvascular platelet thrombi. In this study, we report characterization of mice bearing a targeted disruption of the Adamts13 gene.

Measurement of ADAMTS13 activity and inhibitors.

Purpose Of Review: Acquired or congenital deficiency in the plasma von Willebrand factor-cleaving protease ADAMTS13 causes life-threatening thrombotic thrombocytopenic purpura. This condition is characterized primarily by thrombocytopenia and microangiopathic hemolytic anemia, accompanied by variable degrees of neurologic dysfunction, renal failure, and fever. Measurement of ADAMTS13 activity is important in the diagnosis of microangiopathies such as thrombotic thrombocytopenic purpura.

Identification of strain-specific variants of mouse Adamts13 gene encoding von Willebrand factor-cleaving protease.

Human ADAMTS13 was recently identified as a gene encoding von Willebrand factor-cleaving protease, hADAMTS13. Both congenital and acquired defects in this enzyme can cause thrombotic thrombocytopenic purpura. hADAMTS13 consists of 1,427 amino acid residues and is composed of multiple structural domains including thrombospondin type 1 motifs and CUB domains.

Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome.

We report here 7 new mutations in the ADAMTS13 gene responsible for Upshaw-Schulman syndrome (USS), a catastrophic phenotype of congenital thrombotic thrombocytopenic purpura, by analyzing 5 Japanese families. There were 3 mutations that occurred at exon-intron boundaries: 414+1G>A at intron 4, 686+1G>A at intron 6, and 1244+2T>G at intron 10 (numbered from the A of the initiation Met codon), and we confirmed that 2 of these mutations produced aberrantly spliced messenger RNAs (mRNAs). The remaining 4 mutations were missense mutations: R193W, I673F, C908Y, and R1123C.

Lymphatic absorption of docosahexaenoic acid given as monoglyceride, diglyceride, triglyceride, and ethyl ester in rats.

Lymphatic absorption of docosahexaenoic acids (DHA) given as monoglyceride (MG), consisting of 1(or 3)-species (9 1.4%), 2-species (4.2%) and diglyceride (DG) consisting of 1,3-species (70.