The protease thrombin is required for normal hemostasis and pathologic thrombogenesis. Since the mechanism of coagulation factor XI (FXI)-dependent thrombus growth remains unclear, we investigated the contribution of FXI to thrombus formation in a primate thrombosis model. Pretreatment of baboons with a novel anti-human FXI monoclonal antibody (aXIMab; 2 mg/kg) inhibited plasma FXI by at least 99% for 10 days, and suppressed thrombin-antithrombin (TAT) complex and ␤-thromboglobulin (␤TG) formation measured immediately downstream from thrombi forming within collagen-coated vascular grafts. FXI inhibition with aXIMab limited platelet and fibrin deposition in 4-mm diameter grafts without an apparent increase in D-dimer release from thrombi, and prevented the occlusion of 2-mm diameter grafts without affecting template bleeding times. In comparison, pretreatment with aspirin (32 mg/kg) prolonged bleeding times but failed to prevent graft occlusion, supporting the concept that FXI blockade may offer therapeutic advantages over other antithrombotic agents in terms of bleeding complications. In whole blood, aXIMab prevented fibrin formation in a collagencoated flow chamber, independent of factor XII and factor VII. These data suggest that endogenous FXI contributes to arterial thrombus propagation through a striking amplification of thrombin generation at the thrombus luminal surface. (Blood. 2009;113:936-944) IntroductionBlood coagulation during hemostasis is initiated by the tissue factor (TF)/factor VIIa complex (the extrinsic pathway) that activates factors IX and X, and ultimately produces thrombin at sites of vascular injury. 1 In thrombosis, intravascular blood coagulation may also be initiated by the extrinsic pathway. 2,3 However, impairment of the TF/factor VIIa pathway does not provide full protection from thrombosis, since symptomatic factor VII deficient subjects can develop concurrent thrombosis and severe bleeding. 4 The functions of the contact proteins (factor XI, factor XII, prekallikrein, and high-molecular-weight kininogen) in hemostasis are less clear. The physiologic role of factor XI (FXI) has been difficult to determine because of the variable bleeding disorder associated with FXI deficiency, 5 and because monospecific FXI inhibitors have not been widely available for experimental investigation. FXI activation is thought to proceed through thrombin-and/or factor XIIdependent mechanisms, and activated FXI (FXIa) contributes to sustained thrombin generation after initiation of blood clotting by activating factor IX. These activities ultimately promote coagulation, platelet activation, and preservation of fibrin clot integrity. 6,7 Thrombin also increases the density of fibrin networks 8 and indirectly inhibits fibrinolysis through activation of carboxypeptidase B (thrombin-activatable fibrinolysis inhibitor, TAFI). 9 Thus, FXI may support thrombus propagation and clot stability by increasing thrombin generation. 10,11 Compelling circumstantial evidence suggests a contributory role for FXI in the p...

Pulmonary surfactant lowers surface tension in the lungs. Physiological studies indicate two key aspects of this function: that the surfactant film forms rapidly; and that when compressed by the shrinking alveolar area during exhalation, the film reduces surface tension to very low values. These observations suggest that surfactant vesicles adsorb quickly, and that during compression, the adsorbed film resists the tendency to collapse from the interface to form a three-dimensional bulk phase. Available evidence suggests that adsorption occurs by way of a rate-limiting structure that bridges the gap between the vesicle and the interface, and that the adsorbed film avoids collapse by undergoing a process of solidification. Current models, although incomplete, suggest mechanisms that would partially explain both rapid adsorption and resistance to collapse as well as how different constituents of pulmonary surfactant might affect its behavior.

Although cardiac malformations at birth are typically associated with genetic anomalies, blood flow dynamics also play a crucial role in heart formation. However, the relationship between blood flow patterns in the early embryo and later cardiovascular malformation has not been determined. We used the chicken embryo model to quantify the extent to which anomalous blood flow patterns predict cardiac defects that resemble those in humans and found that restricting either the inflow to the heart or the outflow led to reproducible abnormalities with a dose-response type relationship between blood flow stimuli and the expression of cardiac phenotypes. Constricting the outflow tract by 10-35% led predominantly to ventricular septal defects, whereas constricting by 35-60% most often led to double outlet right ventricle. Ligation of the vitelline vein caused mostly pharyngeal arch artery malformations. We show that both cardiac inflow reduction and graded outflow constriction strongly influence the development of specific and persistent abnormal cardiac structure and function. Moreover, the hemodynamic-associated cardiac defects recapitulate those caused by genetic disorders. Thus our data demonstrate the importance of investigating embryonic blood flow conditions to understand the root causes of congenital heart disease as a prerequisite to future prevention and treatment. Congenital heart defects result from genetic anomalies, teratogen exposure, and altered blood flow during embryonic development. We show here a novel "dose-response" type relationship between the level of blood flow alteration and manifestation of specific cardiac phenotypes. We speculate that abnormal blood flow may frequently underlie congenital heart defects.

Embryonic heart formation results from a dynamic interplay between genetic and environmental factors. Blood flow during early embryonic stages plays a critical role in heart development, as interactions between flow and cardiac tissues generate biomechanical forces that modulate cardiac growth and remodeling. Normal hemodynamic conditions are essential for proper cardiac development, while altered blood flow induced by surgical manipulations in animal models result in heart defects similar to those seen in humans with congenital heart disease. This review compares the altered hemodynamics, changes in tissue properties, and cardiac defects reported after common surgical interventions that alter hemodynamics in the early chick embryo, and shows that interventions produce a wide spectrum of cardiac defects. Vitelline vein ligation and left atrial ligation decrease blood pressure and flow; and outflow tract banding increases blood pressure and flow velocities. These three surgical interventions result in many of the same cardiac defects, which indicate that the altered hemodynamics interfere with common looping, septation and valve formation processes that occur after intervention and that shape the four-chambered heart. While many similar defects develop after the interventions, the varying degrees of hemodynamic load alteration among the three interventions also result in varying incidence and severity of cardiac defects, indicating that the hemodynamic modulation of cardiac developmental processes is strongly dependent on hemodynamic load.

Altered blood flow during embryonic development has been shown to cause cardiac defects; however, the mechanisms by which the resulting haemodynamic forces trigger heart malformation are unclear. This study used heart outflow tract banding to alter normal haemodynamics in a chick embryo model at HH18 and characterized the immediate blood flow response versus the degree of band tightness. Optical coherence tomography was used to acquire two-dimensional longitudinal structure and Doppler velocity images from control (n ¼ 16) and banded (n ¼ 25, 6-64% measured band tightness) embryos, from which structural and velocity data were extracted to estimate haemodynamic measures. Peak blood flow velocity and wall shear rate (WSR) initially increased linearly with band tightness ( p , 0.01), but then velocity plateaued between 40% and 50% band tightness and started to decrease with constriction greater than 50%, whereas WSR continued to increase up to 60% constriction before it began decreasing with increased band tightness. Time of flow decreased with constriction greater than 20% ( p , 0.01), while stroke volume in banded embryos remained comparable to control levels over the entire range of constriction ( p . 0.1). The haemodynamic dependence on the degree of banding reveals immediate adaptations of the early embryonic cardiovascular system and could help elucidate a range of cardiac adaptations to gradually increased load.