Factor XI promotes hemostasis in factor IX-deficient mice.

Essentials Mice lacking factor IX (FIX) or factor XI (FXI) were tested in a saphenous vein bleeding model. FIX-deficient mice displayed a hemostatic defect and FXI-deficient mice were similar to wild type mice. Infusion of FXI or over-expression of FXI in FIX-deficient mice improved hemostasis. FXI may affect the phenotype of FIX-deficiency (hemophilia B). SUMMARY: Background In humans, deficiency of coagulation factor XI may be associated with a bleeding disorder, but, until recently, FXI-deficient mice did not appear to have a hemostatic abnormality. A recent study, however, indicated that FXI-deficient mice show a moderate hemostatic defect in a saphenous vein bleeding (SVB) model. Objectives To study the effect of FXI on bleeding in mice with normal levels of the FXI substrate FIX and in mice lacking FIX (a murine model of hemophilia B). Methods Wild-type mice and mice lacking either FIX (F9- ) or FXI (F11-/- ) were tested in the SVB model. The plasma levels of FXI in F11-/- mice were manipulated by infusion of FXI or its active form FXIa, or by overexpressing FXI by the use of hydrodynamic tail vein injection. Results F9- mice showed a significant defect in the SVB model, whereas F11-/- mice and wild-type mice were indistinguishable. Intravenous infusion of FXI or FXIa into, or overexpression of FXI in, F9- mice improved hemostasis in the SVB model. Overexpression of a FXI variant lacking a FIX-binding site also improved hemostasis in F9- mice. Conclusions Although we were unable to demonstrate a hemostatic defect in F11-/- mice in the SVB model, our results support the premise that supraphysiological levels of FXI improve hemostasis in F9- mice through FIX-independent pathways.

Observation of neutronless fusion reactions in picosecond laser plasmas.

The yield of alpha particles in neutronless fusion reactions 11B +p in plasmas produced by picosecond laser pulses with the peak intensity of 2 x 10(18) W/cm2 has been observed. Experiments were carried out on the "Neodymium" laser facility at the pulse energy of 10-12 J and pulse duration of 1.5 ps. The composite targets 11B + (CH2)n were used. The yield of 10(3) alpha particles per pulse has been observed. The energy spectrum of alpha particles contains two maxima: at 3-4 MeV and at 6-10 MeV . The first of these peaks corresponds to the secondary alpha12 particles at the decay of the intermediate first excited state of 8Be, whereas the second peak demonstrates generation of alpha1 particles in the reaction 11B +p with the production of this excited state. Simultaneous measurements of neutrons result in zero yield, which proves the observation of neutronless fusion reactions in our experiments.

Influence of optical thickness and hot electrons on Rydberg spectra of Ne-like and F-like copper ions.

Spectra in the 7.10 to 8.60 A range from highly charged copper ions are observed from three different laser-produced plasmas (LPPs). The LPPs are formed by a 15-ns Nd:glass laser pulse (type I: E(pulse)=1-8 J, lambda=1.064 microm), a 1-ps Nd:glass laser pulse (type II: E(pulse)=1 J, lambda=1.055 microm), and a 60-fs Ti:sapphire laser pulse (type III: E(pulse)=800 mJ, lambda=790 nm). The spectra of high-n (n

Analysis of high- n dielectronic Rydberg satellites in the spectra of Na -like Zn XX and Mg -like Zn XIX.

We have observed spectra from highly charged zinc ions in a variety of laser-produced plasmas. Spectral features that are Na - and Mg -like satellites to high- n Rydberg transitions in the Ne -like Zn XXI spectrum are analyzed and modeled. Identifications and analysis are made by comparison with highly accurate atomic structure calculations and steady state collisional-radiative models. Each observed Zn XX and Zn XIX feature comprises up to approximately 2 dozen individual transitions, these transitions are excited principally by dielectronic recombination through autoionizing levels in Na - and Mg -like Zn19+ and Zn18+. We find these satellites to be ubiquitous in laser-produced plasmas formed by lasers with pulse lengths that span four orders of magnitude, from 1 ps to approximately 10 ns. The diagnostic potential of these Rydberg satellite lines is demonstrated.

Prolylcarboxypeptidase independently activates plasma prekallikrein (fletcher factor).

Prolylcarboxypeptidase isoform 1 (PRCP1) is capable of regulating numerous autocrines and hormones, such as angiotensin II, angiotensin III, αMSH1-13, and DesArg(9) bradykinin. It does so by cleaving a C-terminal PRO-X bond. Recent work also indicates that the human PRCP1 activates plasma prekallikrein (PK) to kallikrein on endothelial cells through an uncharacterized mechanism. This study aims to identify PRCP1 binding interaction and cleavage site on PK. Recently, a cDNA encoding a novel splice variant of the human PRCP1 was identified. This isoform differed only in the N-terminal region of the deduced amino acid sequence. Using structural and functional studies, a combination of peptide mapping and site-directed mutagenesis approaches were employed to investigate the interaction of PRCP1 with PK. Three PRCP peptides, in decreasing order of potency, from 1) the N-terminus of the secreted protein, 2) spanning the opening of the active site pocket, and 3) in the dimerization region inhibit PRCP activation of PK on endothelial cells. Investigations also tested the hypothesis that PRCP cleavage site on PK is between its C-terminal Pro 637 (P(637)) and Ala 638 (A(638)). Recombinant forms of PK with C-terminal alanine mutagenesis or a stop codon is activated equally as wild type PK by PRCP. In conclusion, PRCP1 interacts with PK at multiple sites for PK activation. PRCP1 also enhances FXIIa activation of PK, suggesting that its activation site on PK is not identical to that of FXIIa.

Evidence for factor IX-independent roles for factor XIa in blood coagulation.

BACKGROUND: Factor XIa is traditionally assigned a role in FIX activation during coagulation. However, recent evidence suggests this protease may have additional plasma substrates. OBJECTIVE: To determine whether FXIa promotes thrombin generation and coagulation in plasma in the absence of FIX, and to determine whether FXI-deficiency produces an antithrombotic effect in mice independently of FIX. METHODS: FXIa, FXIa variants and anti-FXIa antibodies were tested for their effects on plasma coagulation and thrombin generation in the absence of FIX, and for their effects on the activation of purified coagulation factors. Mice with combined FIX and FXI deficiency were compared with mice lacking either FIX or FXI in an arterial thrombosis model. RESULTS: In FIX-deficient plasma, FXIa induced thrombin generation, and anti-FXIa antibodies prolonged clotting times. This process involved FXIa-mediated conversion of FX and FV to their active forms. Activation of FV by FXIa required the A3 domain on the FXIa heavy chain, whereas activation of FX did not. FX activation by FXIa, unlike FIX activation, was not a calcium-dependent process. Mice lacking both FIX and FXI were more resistant to ferric chloride-induced carotid artery occlusion than FXI-deficient or FIX-deficient mice. CONCLUSION: In addition to its predominant role as an activator of FIX, FXIa may contribute to coagulation by activating FX and FV. As the latter reactions do not require calcium, they may make important contributions to in vitro clotting triggered by contact activation. The reactions may be relevant to FXIa's roles in hemostasis and in promoting thrombosis.