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Introduction Factor XII (FXII) is the zymogen of serine protease factor XIIa (FXIIa). Discovered by Ratnoff 60 years ago, FXII was first recognized as essential for surface-activated blood coagulation. FXII [...], Coagulation factor XII (FXII) deficiency Is associated with decreased neutrophil migration, but the mechanisms remain uncharacterized. Here, we examine how FXII contributes to the inflammatory response. In 2 models of sterile inflammation, FXII-deficient mice ([F12.sup.-/-]) had fewer neutrophils recruited than WT mice. We discovered that neutrophils produced a pool of FXII that is functionally distinct from hepatic-derived FXII and contributes to neutrophil trafficking at sites of inflammation. FXII signals in neutrophils through urokinase plasminogen activator receptor-mediated (uPAR-mediated) Akt2 phosphorylation at [S.sup.474] ([pAktS.sup.474]). Downstream of [pAkt2S.sup.474], FXII stimulation of neutrophils upregulated surface expression of [[alpha].sub.M][[beta].sub.2] integrin, increased intracellular calcium, and promoted extracellular DNA release. The sum of these activities contributed to neutrophil cell adhesion, migration, and release of neutrophil extracellular traps in a process called NETosis. Decreased neutrophil signaling in [F12.sup.-/-] mice resulted in less inflammation and faster wound healing. Targeting hepatic F12 with siRNA did not affect neutrophil migration, whereas WT BM transplanted into [F12.sup.-/-] hosts was sufficient to correct the neutrophil migration defect in [F12.sup.-/-] mice and restore wound inflammation. Importantly, these activities were a zymogen FXII function and independent of FXIIa and contact activation, highlighting that FXII has a sophisticated role in vivo that has not been previously appreciated.

Author(s): Karim Asehnoune [sup.1] [sup.2], David Faraoni [sup.3], Karim Brohi [sup.4] Author Affiliations: (1) grid.277151.7, 0000000404720371, Pôle PHU3, Service d'Anesthésie Réanimation Chirurgicale, Hôtel Dieu, CHU Nantes, , 44035, Nantes cedex [...]

Combined deficiency of coagulation factors V and VIII (F5F8D), an autosomal recessive disorder characterized by coordinate reduction in the plasma levels of factor V (FV) and factor VIII (FVIII), is genetically linked to mutations in the transmembrane lectin ERGIC-53 and the soluble calcium-binding protein MCFD2. Growing evidence indicates that these two proteins form a complex recycling between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment and thereby function as a cargo receptor in the early secretory pathway of FV and FVIII. For better understanding of the mechanisms underlying the functional coordination of ERGIC-53 and MCFD2, we herein characterize their interaction by x-ray crystallographic analysis in conjunction with NMR and ultracentrifugation analyses. Inspection of the combined data reveals that ERGIC-53-CRD binds MCFD2 through its molecular surface remote from the sugar-binding site, giving rise to a 1:1 complex in solution. The interaction is independent of sugar-binding of ERGIC-53 and involves most of the missense mutation sites of MCFD2 so far reported in F5F8D. Comparison with the previously reported uncomplexed structure of each protein indicates that MCFD2 but not ERGIC-53-CRD undergoes significant conformational alterations upon complex formation. Our findings provide a structural basis for the cooperative interplay between ERGIC-53 and MCFD2 in capturing FV and FVIII. MCFD2 | ERGIC-53 | calcium-binding protein | cargo receptor | intracellular lectin doi/10.1073/pnas.0908526107

A study was conducted to investigate the efficacy of rivaroxaban, an orally active direct factor Xa inhibitor, in preventing venous thrombosis after total knee arthroplasty. Findings concludes with the note that rivaroxaban is superior to enoxaparin for thromboprophylaxis after total knee arthroplasty.

A study was conducted to examine the phase 3 trials, which compares the efficacy and safety of rivaroxaban, an oral direct inhibitor of factor Xa with enoxaparin in patients undergoing total hip arthroplasty. Findings observed that 10-mg oral dose of rivaroxaban are more effective for extended thromboprophylaxis than 40-mg subcutaneous dose of enoxaparin in patients undergoing elective total hip arthroplasty.

Thrombin is clearly a key trigger of thrombosis, the proximal cause of most morbidity and mortality in atherosclerotic cardiovascular disease. Might thrombin also contribute to longer-term, structural changes in the [...]

For the parents of a child born with haemophilia, the diagnosis comes with both good and bad news. The good news is that the child, at least if he (or [...]

Byline: Philip Arnold (1), Sue Jackson (2), Jonathan Wallis (3), Jon Smith (4), David Bolton (5), Simon Haynes (6) Keywords: Extra-corporeal membrane oxygenation Coagulation Bleeding Blood transfusion Abstract: Objective: To ascertain the activity of major coagulation factors during the first 24 h of extra-corporeal membrane oxygenation (ECMO) used to support hypoxaemic neonates. Design and setting: A prospective observational study in a regional centre for ECMO and paediatric cardiac surgery, placing 15--20 neonates on ECMO per year. Patients: Ten neonates receiving ECMO for severe hypoxaemia. Measurement and results: The activity of major clotting factors, of the inhibitor anti-thrombin III and of markers of blood activation were measured during the first 24 h of neonatal extra-corporeal membrane oxygenation (ECMO) and prior to initiation of ECMO. There was laboratory evidence of factor deficiency and of activation of coagulation at all stages. The initiation of ECMO leads to an initial worsening of coagulopathy, but factor deficiency and abnormal activation of coagulation is also seen prior to ECMO in these very sick neonates. Conclusion: If factor deficiency is to be avoided a pro-active approach is required to rapidly correct factor activity. This would include the use of fresh frozen plasma. The effect of such an approach on outcome is at yet uncertain. Author Affiliation: (1) Department of Anaesthesia, Alder Hey (Royal Liverpool Children's Hospital), Eaton Road, Liverpool L12 2AP, UK (2) Department of Anaesthesia, Newcastle General Hospital, Westgate Road, Newcastle-upon-Tyne, UK (3) Department of Haematology, Freeman Hospital, Freeman Road, Newcastle-upon-Tyne, UK (4) Department of Cardiothoracic Anaesthesia and Intensive Care, Freeman Hospital, Freeman Road, Newcastle-upon-Tyne, UK (5) Department of Cardiothoracic Anaesthesia and Intensive Care, Freeman Hospital, Freeman Road, Newcastle-upon-Tyne, UK (6) Department of Cardiothoracic Anaesthesia and Intensive Care, Freeman Hospital, Freeman Road, Newcastle-upon-Tyne, UK Article History: Received Date: 21/12/2000 Accepted Date: 30/04/2001 Article note: Final revision received: 6 April 2001 Electronic Publication

Many patients with a history of deep vein thrombosis may have elevated blood levels of factor XI. Factor XI is involved in blood clotting, which is abnormal in patients with deep vein thrombosis. These patients have excessive clotting, and are predisposed to develop blood clots in their legs. In a study of 474 patients with deep vein clotting and 474 healthy volunteers, those who had the highest factor XI levels had twice the risk of deep vein thrombosis as those with the lowest levels.

Variants of the coagulation factor VII gene may affect the level of clotting protein in the blood and the rate of heart attack. Researchers compared 165 patients who had a heart attack as well as a close family history of cardiovascular disease with 225 patients with no such history. Particular variants of the coagulation factor VII gene were associated with increased risk for heart attack. Patients with the lowest risk of heart attack had other variants of the gene and the lowest levels of factor VII. The gene may regulate factor VII levels and thus have an effect on heart attack risk.

Byline: Alex Veldman (1), Doris Fischer (1), Burkhard Voigt (1), Peter A. Beyer (2), Rolf Schlosser (1), Antje Allendorf (1), Wolfhardt Kreuz (1) Keywords: Shock Bleeding Neonate Coagulation Multi-transfusion Abstract: Abstract Objective. Massive hemorrhage with shock is a common problem for the intensivist. The use of recombinant activated factor VII (rFVIIa), known as efficient treatment for hemophilia, has been reported to control severe bleeding episodes in critically care patients, but never in preterm neonates. Design. Case report (two cases) and review of the literature. Setting. Neonatal intensive care unit, university teaching hospital. Patients. Two preterm neonates with life-threatening hemorrhages, from the liver and spleen in one patient and from the lung in the other. Intervention. Intravenous administration of 150/200 Aug/kg of rFVIIa (Novoseven, NovoNordisk, Copenhagen, Denmark). Measurements and results. Complete hemostasis 10 min after the second bolus in the two patients. Conclusion. For the intensivist, the successful use of rFVIIa in these patients and others lacking pre-existing coagulopathies points to rFVIIa as a novel therapeutic approach for patients presenting with massive life-threatening hemorrhage. Author Affiliation: (1) Department of Pediatrics, Division of Neonatalogy, J. W. Goethe University Hospital, Theodor Stern Kai 7, 60590 Frankfurt/Main, Germany (2) Department of Pediatric Surgery, J. W. Goethe University Hospital, Theodor Stern Kai 7, 60590 Frankfurt/Main, Germany Article History: Received Date: 25/03/2002 Accepted Date: 05/08/2002 Article note: Electronic Publication

Recent studies have demonstrated the efficacy of recombinant activated factor VIIa (rFVIIa) patients with hemophilia and inhibitors. The use of rFVIIa as a hemostatic agent has been extended to a [...], The case of a preterm infant weighing 1120 g who successfully received recombinant activated factor VII (rFVIIa) without complication for control of a life-threatening bleeding event resulting from a ruptured umbilical artery is reported. After performing an exploratory laparotomy at 27 hours of age, hemorrhage from the surgical wound and various sites persisted. By 63 hours of age, the infant had received a total of 192 mL (171 mL/kg) of packed red blood cells, 115 mL (103 mL/kg) of fresh frozen plasma, 8 mL of cryoprecipitate, and 75 mL (67 mL/kg) of platelet concentrate without stabilization. Hemorrhage ceased after 2 doses of 40 µ g/kg/dose recombinant activated factor VII given at 63 and 70 hours of age, with subsequent stabilization of the hematocrit and without need for additional transfusion therapy. Pediatrics 2002;107:169-171; rFVIIa, preterm, bleeding.

Byline: R. Rauch (1), M. Hofbeck (1), M. Ries (1), H. Singer (1), J. Klinge (1) Keywords: Key words Prothrombin-complex concentrate; Oral anticoagulation; Fresh frozen plasma; Liver dysfunction; Heart surgery Abstract: A 17-year-old patient with Shone's disease had to be readmitted to the hospital 3 months after implantation of an artificial aortic valve because of extreme mitral insufficiency with consecutive pulmonary edema and hepatic dysfunction. He had been orally anticoagulated and presented with a high international normalized ratio of 6.7. Emergency replacement of the mitral valve was possible only after administration of prothrombin-complex concentrate, as vitamin K.sub.1 and fresh frozen plasma did not correct the hemostatic defect sufficiently. Author Affiliation: (1) Klinik fur Kinder und Jugendliche der Friedrich-Alexander-Universitat Erlangen-Nuernberg, Loschgestrasse 15, 91 054 Erlangen, Germany Tel.: + 49 (91 31) 8 53--31 18 or 31 19 Fax: + 49 (91 31) 8 53--31 13, DE Article note: Received: 14 October 1998/Accepted: 13 April 1999

Bernard-Soulier syndrome (BSS) was first recognized in 1948 by two French hematologists--Jean Bernard and Jean Pierre Soulier. They described a patient from a consanguineous family afflicted with severe bleeding episodes, [...], Bernard-Soulier syndrome is an inherited platelet disorder, which is transmitted in an autosomal recessive manner. This syndrome is characterized by variable thrombocytopenia and large defective platelets. Bernard-Soulier syndrome often presents early with bleeding symptoms, such as epistaxis, ecchymosis, menometrorrhagia, and gingival or gastrointestinal bleeding. Diagnosis can be confirmed by platelet aggregation studies and flow cytometry. The differential diagnosis includes the other inherited giant platelet disorders, as well as von Willebrand disease and immune thrombocytopenia purpura. Treatment is generally supportive with platelet transfusions when absolutely necessary and avoidance of antiplatelet medications. Recombinant activated factor VII and desmopressin have been used in attempts to shorten bleeding times; however, no definitive studies regarding their effectiveness have been reported. (Arch Pathol Lab Med. 2007;131:1834-1836)