A Quantitative and Mechanistic Assessment of Activated Thrombin-Activatable Fibrinolysis Inhibitor and its Role in Pathological Bleeding and Thrombosis

The coagulation and fibrinolytic systems are linked by the thrombin-thrombomodulin complex which regulates each system through activation of protein C and TAFI, respectively. We have used novel assays and techniques to study the enzymology and biochemistry of TAFI and TAFIa, to measure TAFI activation in hemophilia A and protein C deficiency and to determine if enhancing TAFI activation can improve hemostasis in hemophilic plasma and whole blood. We show that TAFIa not TAFI attenuates fibrinolysis in vitro and this is supported by a relatively high catalytic efficiency (16.41μM-1s-1) of plasminogen binding site removal from fibrin degradation products (FDPs) by TAFIa. Since the catalytic efficiency of TAFIa in removing these sites is ~60-fold higher than that for inflammatory mediators such as bradykinin it is likely that FDPs are a physiological substrate of TAFIa. The high catalytic efficiency is primarily a result of a low Km which can be explained by a novel mechanism where TAFIa forms a binary complex with plasminogen and is recruited to the surface of FDPs. The low Km also suggests that TAFIa would effectively cleave lysines from FDPs during the early stages of fibrinolysis (i.e. at low concentrations of FDPs). Since individuals with hemophilia suffer from premature fibrinolysis as a result of insufficient TAFI activation we quantified TAFI activation in whole blood from hemophilic subjects. Both the rate of activation and the area under the TAFI activation time course (termed TAFIa potential) was determined to be reduced in hemophilia A and the TAFIa potential was significantly and inversely correlated with the clinical bleeding iii phenotype. Using a novel therapeutic strategy, we used soluble thrombomodulin to increase TAFI activation which improved the clot lysis time in factor VIII deficient human plasma and hemophilic dog plasma as well as hemophilic dog blood. Finally, we briefly show in a biochemical case study that TAFI activation is enhanced in protein C deficiency and when afflicted individuals are placed on Warfarin anticoagulant therapy, TAFI activation is reduced. Since TAFIa stabilizes blood clots, this suggests that reducing TAFI activation or inhibiting TAFIa may help restore blood flow in vessels with pathological thrombosis.

"The Black Imprint of Sandals in White Mosaic Floors": H.D.'s Mythomystical Poetics

My dissertation examines the traces of inverse (mytho)mysticism, more synchronous with mythical alchemy than transcendent mystery, in H.D.’s mature work (1946-1961). Whereas H.D.’s earliest works respond to a fin de siècle occultism and a collective psyche troubled by the eschatological distress that, as Susan Acheson writes, “was widespread amongst modernist writers grappling with …world events and with the implications of Nietzsche’s inaugural annunciation of modernity in terms of the death of God” (187), her later oeuvre is dedicated to the same work of soul undertaken by the “secret cult of Night” in Vale Ave. Here, her thematic scope faces two ways: backward to ancient Greek mystery cults and their palingenesic rites and forward to depth psychologists searching for the Soul of the World. Vale Ave plays a pronounced role in my study as symbolic guide; in its seventy-four sequences the layering of time in the “trilogy” of past, present, and future that H.D. had explored during the years of the Second World War in order to get behind the fallen walls of cause and effect collapses into two distinct phases of human origin—“meeting” (evolution) and “parting” (involution)—and the poem invites Lilith and Lucifer to be its archetypal guides. My method for the study is imaginal, entering such disciplines as history, philosophy, and theology and bringing psychological understanding to them. John Walsh’s introduction to Vale Ave notes H.D.’s theme “that the human psyche exists in a dimension outside of time and space as well as within them. In Vale Ave, H.D. presents the extremity of this dual-dimensionality: metempsychosis” (vii). However, the concept that H.D. investigates is more than a literary processus of characters who adopt different masks and appear at various junctures in a chronological unwinding of history. I explore H.D.'s works as part of a Modernist tradition of writing “books of the dead” designed not to guide the soul after death, but to draw the gaze upon “a nearer thing,” as H.D. writes in Erige Cor Tuum Ad Me In Caelum, the wisdom intrinsic in the spirit of life itself.