Maurizio Tomaiuolo's research while affiliated with Wills Eye Hospital and other places

Publications (23)

Article
The critical role of GRK2 in regulating cardiac function has been well documented for over three decades. Therefore, targeting GRK2 has been extensively studied as a novel approach to treat cardiovascular disease. However, little is known about its role in hemostasis and thrombosis. Here we provide the first evidence that GRK2 limits platelet activ...
Article
Rebalancing of the hemostatic system by targeting endogenous anticoagulant pathways, like the Protein C system, is being tested as a means of improving hemostasis in patients with hemophilia. Recent intravital studies of hemostasis demonstrated that, in some vascular contexts, thrombin activity is sequestered to the extravascular compartment. These...
Article
Background TFPI is an essential regulator of coagulation, limiting thrombin generation and preventing thrombosis. In humans and mice, TFPIα is the sole isoform present in platelets. Objective Here we asked whether TFPIα, because of its release from platelets at sites of injury, has a unique role in limiting the hemostatic response. Methods TFPIα-...
Article
Hemostasis is an innate protective mechanism that plays a central role in maintaining the homeostasis of the vascular system during vascular injury. Studying this essential physiological process is often challenged by the difficulty of modeling and probing the complex dynamics of hemostatic responses in the native context of human blood vessels. To...
Article
Electron microscopy has been a valuable tool for the study of platelet biology and thrombosis for more than 70 years. Early studies using conventional transmission and scanning electron microscopy (EM) provided a foundation for our initial understanding of platelet structure and how it changes upon platelet activation. EM approaches have since been...
Article
Extensive studies have detailed the molecular regulation of individual components of the hemostatic system, including platelets, coagulation factors, and regulatory proteins. Questions remain, however, about how these elements are integrated at the systems level within a rapidly changing physical environment. To answer some of these questions, we d...
Article
Full-text available
All-electronic DNA biosensors based on graphene field effect transistors (GFETs) offer the prospect of simple and cost-effective diagnostics. For GFET sensors based on complementary probe DNA, the sensitivity is limited by the binding affinity of the target oligonucleotide, in the nM-range for 20-mer targets. We report a ~20,000× improvement in sen...
Article
We have previously shown in the microcirculation that gradients of platelet agonists develop during the hemostatic response as a consequence of the solute transport properties within the evolving platelet mass. These agonist gradients result in the formation of a gradient of platelet activation extending from the site of vascular injury. Here we ut...
Article
Endogenous anticoagulants, including antithrombin III, tissue factor pathway inhibitor, and activated protein C (aPC) provide a biochemical means to inhibit thrombin generation and/or activity. In addition, we have previously shown that platelet mass retraction prevents the escape and exchange of solutes, thereby providing a biophysical mechanism t...
Article
Background: Hemostasis studies performed in vivo have shown that hemostatic plugs formed after penetrating injuries are characterized by a core of highly-activated densely-packed platelets near the injury site, covered by a shell of less-activated and loosely-packed platelets. Thrombin production occurs near the injury site, further activating pla...
Article
Previous studies using intravital microscopy have shown that hemostatic plugs formed in the mouse microvasculature have a characteristic architecture in which the extent of platelet activation reflects gradients in the distribution of platelet agonists radiating outwards from the injury site. In that setting, we found minimal overlap of thrombin an...
Chapter
An essential part of the hemostatic response to injury is a well-calibrated accumulation of activated platelets. Here we will consider, first, how individual signaling and regulatory pathways in platelets combine to produce a flexible signaling network that can respond appropriately to injury under conditions that range from the macro- to the micro...
Article
Hemostasis requires tightly regulated interaction of the coagulation system, platelets, blood cells, and vessel wall components at a site of vascular injury. Dysregulation of this response may result in excessive bleeding if the response is impaired, and pathologic thrombosis with vessel occlusion and tissue ischemia if the response is robust. Stud...
Article
Full-text available
It is unknown if a lower size limit exists for human blood coagulation under flow over physiological vessel wall triggers as small as a single collagen fiber. Prior determinations of the smallest sized surface stimuli necessary for clotting of human blood, defined as the patch size threshold, have not deployed whole blood, hemodynamic flow, and pla...
Article
Full-text available
Inflammation is a complex process driven by the coordinated action of a vast number of pro- and anti-inflammatory molecular mediators. While experimental studies have provided an abundance of information about the properties and mechanisms of action of individual mediators, essential system-level regulatory patterns that determine the time-course o...
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Full-text available
Hemostatic thrombi develop a characteristic architecture in which a core of highly activated platelets is covered by a shell of less-activated platelets. Here we have used a systems biology approach to examine the interrelationship of this architecture with transport rates and agonist distribution in the gaps between platelets. Studies were perform...
Article
Hemostatic thrombi formed after a penetrating injury have a heterogeneous architecture in which a core of highly activated, densely packed platelets is covered by a shell of less-activated, loosely packed platelets. In the first manuscript in this series, we show that regional differences in intrathrombus protein transport rates emerge early in the...
Article
Hemostatic thrombi formed after a penetrating injury have a distinctive structure in which a core of highly activated, closely packed platelets is covered by a shell of less-activated, loosely packed platelets. We have shown that differences in intrathrombus molecular transport emerge in parallel with regional differences in platelet packing densit...
Article
Full-text available
Hemorrhagic shock is a leading cause of death following severe trauma, and platelet transfusions are frequently necessary to achieve hemostasis. Platelets, however, require special storage conditions, and storage time has been associated with loss of platelet quality. We hypothesized that standard storage conditions have a deleterious effect on pla...
Article
Once released into the circulation by megakaryocytes, circulating platelets can undergo rapid activation at sites of vascular injury and resist unwarranted activation, which can lead to heart attacks and strokes. Historically, the signaling mechanisms underlying the regulation of platelet activation have been approached as a collection of individua...

Citations

... The anxiety around assessing safety is largely due to basic scientific and fundamental mechanisms underlying hemostasis remaining undefined. The study of hemostasis in vitro will require development of microfluidic models of hemostatic plug formation, termed "bleeding chips,"39 to study the spatial dynamics and cell biology of hemostasis under shear flow and samples with variable platelet counts.[39][40][41] The continued development of techniques such as photolithography to generate relevant vascular bed-specific geometries that can be endothelialized may be used to study pathways that protect against vascular leakage, to identify targets, and to test agents that enhance the hemostatic function of platelets, endothelial cells, and the coagulation cascade without causing thrombosis.4,31,42 ...
... It can be expected that electron microscopy and CLEM techniques will become indispensable to study aspects of vascular dynamics in the future (Tomaiuolo et al. 2020). ...
... In circulation, platelets modulate an immune response [1][2][3] and maintain the integrity of the endothelial cell lining of the vascular system as part of the coagulation process in hemostasis [4,5]. Stored platelets play a key role in transfusion medicine. ...
... The continued development of techniques such as photolithography to generate relevant vascular bed-specific geometries that can be endothelialized may be used to study pathways that protect against vascular leakage, to identify targets, and to test agents that enhance the hemostatic function of platelets, endothelial cells, and the coagulation cascade without causing thrombosis.4,31,42 Novel in vivo models are required to study bleeding observed in vascular beds with high fibrinolytic activity and variable pressure gradients, which are critical in terms of patient safety and health; these new models would complement the current models of hemostatic plug formation in the setting of experimental trauma (such as punctures, tail clippings, and lacerations to the forearm).43,44 A mechanistic understanding of thrombosis has facilitated the development of antithrombotic agents, targeting either platelets or the coagulation cascade, for use in the prevention and treatment of cardiovascular diseases. ...
... Comments by M. Tomaiuolo and L.F. Brass raise important questions about the role of mathematical modelling in the attempts to understand hemostasis and thrombosis [4]. The main thesis that modelling and simulations should be predictive is illustrated with several examples related to thrombin generation assays, extrinsic and intrinsic coagulation pathways, platelet aggregation. ...
... The graphene channel, as shown in Figure 1b, was defined by photolithography and oxygen plasma etching. The GFET chip was then annealed in an Ar/H 2 atmosphere to remove any photoresist residues on the graphene channels [34]. The high quality of the as-fabricated GFETs was verified by the negligible D peak (~1345 cm −1 ) in the Raman spectrum ( Figure 1c) [35]. ...
... Considering the thrombus permeability is very small (the inverse of viscous resistance), Fig. 3 (a) demonstrates that the computed velocity in the thrombus is in the (1 × 10 −6 m∕s) which was found of the same order reported in Mirramezani et al. (2018) . Fig. 3 (b) illustrates the concentration of UP which reduces almost linearly along the length of thrombus. ...
... Platelets are the smallest anucleate blood cells, 2-4 mm in size that play a pivotal role in hemostasis and thrombosis. Their main function is to prevent blood loss by forming sticky platelet aggregates (a hemostatic plug) at the site of vascular injury (Brass et al., 2017;Rosen et al., 2001). The initial interaction of platelets with the exposed sub-endothelium at a vessel injury site is mediated by the receptor glycoproteins GPIb-IX-V, GPVI, GPIa/IIa (integrin a2b1) followed by intracellular signaling that promotes platelet adhesion and aggregation. ...
... Thrombi are formed by subsequent platelet aggregation and activation of the coagulation system. [1][2][3] The release of tissue factor (TF) from atherosclerotic plaques and turbulent blood flow in the poststenotic segment of the atherosclerotic artery further contributes to thrombus formation. 4 While previous studies have focused on the role of endothelium, platelets, and fibrin in thrombosis, recent studies have shown that leukocytes and inflammation also contribute to coagulation and thrombosis. ...
... Reduced g'-fibrinogen levels have been associated with an increased venous thrombosis risk [15,41] Here, we demonstrated a simplified ODEs model to simulate the thrombin and fibrin generation. This reduced model may be particularly useful in 49 multiscale simulations that seek to account for single platelet phenomenon [65], microscopic attributes of a wound site [56], and whole vessel dynamics [25,35]. ...