Objective: Clozapine is substantially underutilized in most countries and clinician factors including lack of knowledge and concerns about adverse drug effects (ADEs) contribute strongly to treatment reluctance. The aim of this systematic review was to provide clinicians with a comprehensive information source regarding clozapine ADEs.Methods: PubMed and Embase databases were searched for English language reviews concerned with clozapine ADEs; publications identified by the automated search were manually searched for additional relevant citations. Following exclusion of redundant and irrelevant reports, pertinent information was summarized

Hemostasis and thrombosis are now increasingly recognized as integrally related to blood rheology and blood flow. Platelets, for example, are known to access the vessel wall in ways which depend upon the small‐scale motions of neighboring erythrocytes, and access one another via collisions driven by gradients in blood flow velocity. In this context, flow devices have become a subject of great interest in the clinical assessment of bleeding disorders, especially platelet function defects and von Willebrand disease. While these devices currently lack standardization and outcomes measures which establish clear clinical utility, their promise remains great, particularly in the potential to simulate the microenvironment of arteries vs. veins and in their ability to incorporate such intrinsically flow‐dependent phenomena as co‐localization of tissue‐factor‐bearing microparticles with platelets, the weakness of the GPIb‐vWF bond at very high shear stresses, and even the hemostatic and antithrombotic function of vascular endothelium. In contrast, currently utilized assays are often performed under static conditions that do not involve flow and therefore are not able to simulate the microenvironment of arteries and veins. Am. J. Hematol., 2012. © 2012 Wiley Periodicals, Inc.

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Mural platelet thrombi are considered to facilitate hemostasis in hemophilia via rFVIII/ rFVIIa binding to platelet membranes with enhancement of local fibrin deposition. We therefore sought to show that Factors VIII and VIIa co-localize to platelet membranes of adherent platelet aggregates and promote local deposition of fibrin. We collected blood from 9 patients with severe hemophilia A just prior to a prophylactic dose of rFVIII, and from 8 normals, into a plastic tube containing 5 U/ml FC low MW heparin, 1.75 µg/ml of the Tab (anti-CD41) mo antibody, and 1.0 μg/ml of ALEXA 555-conjugated rabbit anti-mouse secondary antibody, plus 0, 11, 33 or 100 ng/ml rFVIII-Oregon green. Similar approaches were used for rFVIIa or fibrin. Fibrin was detected using the monoclonal antibody 59D8 directed against human β fibrin, together with the above Alexa555-conjugated rabbit anti-mouse secondary antibody, and co-localized to platelet aggregate surfaces using 10 µM quinicrine dihydrochloride. Blood at 37° C was withdrawn at 270 sec-1 through a flow chamber, over 150 µm glass cover slips with preadsorbed microfibrillar collagen, using epifluorescence video microscopy and digital image analysis (MetaMorph Premier software). Added rFVIII or rFVIIa co-localized (Fig. 1) with platelet membranes and increased with rFVIII concentration. With hemophiliac blood and 100 ng/ml rFVIII, percent co-localization at 7 min was 52.6 ± 7.7 (N=4). Platelet aggregate growth rate, image pixels/min from time 3 to 9 min, was 26% lower in hemophiliac blood, but increased (p = 0.0001) 2.34 ± 0.62 (6)-fold with rFVIII, and (p = 0.0005) 1.91 ± 0.56 (6)-fold with 30 nM rFVIIa (Fig. 2). These increases essentially restored (or only slightly augmented) platelet deposition to levels observed in normal blood. In contrast, the effect on local fibrin deposition was profound: fibrin deposition was delayed by 3-5 min in normal blood, but by >13 min in hemophiliac blood. Addition of rFVIII or rFVIIa shortened the latter time to 7-9 min. Increases in platelet aggregate growth rate, following a lag phase in growth rate, paralleled the onset of fibrin formation. Fibrin appeared as comet-shaped deposits (comet head 20-25 µm in diameter) centered over each platelet aggregate (3-10 µm), the comet tail trailing 60-75 µm downstream (Fig. 3). In flowing whole blood in real time, these data show that rFVIII and rFVIIa co-localize with platelet membranes of activated, surface-adherent platelet aggregates, and support fibrin deposition in the slow-flow wakes immediately surrounding the platelet aggregates. Disclosures Grabowski: CSL Behring: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk, Denmark: Research Funding. Gunnarsson:Novo Nordisk: Employment. Ezban:Novo Nordisk: Employment.