Starting 90 years ago with a clinical description by Glanzmann of a bleeding disorder associated with a defect in platelet function, technologic advances helped investigators identify the defect as a mutation(s) in the integrin family receptor, αIIbβ3, which has the capacity to bind fibrinogen (and other ligands) and support platelet-platelet interactions (aggregation). The receptor's activation state was found to be under exquisite control, with activators, inhibitors, and elaborate inside-out signaling mechanisms controlling its conformation. Structural biology has produced high-resolution images defining the ligand binding site at the atomic level. Research on αIIbβ3 has been bidirectional, with basic insights resulting in improved Glanzmann thrombasthenia carrier detection and prenatal diagnosis, assays to identify single nucleotide polymorphisms responsible for alloimmune neonatal thrombocytopenia, and the development of αIIbβ3 antagonists, the first rationally designed antiplatelet agents, to prevent and treat thrombotic cardiovascular disease. The future looks equally bright, with the potential for improved drugs and the application of gene therapy and stem cell biology to address the genetic abnormalities. The αIIbβ3 saga serves as a paradigm of rigorous science growing out of careful clinical observations of a rare disorder yielding both important new scientific information and improved diagnosis, therapy, and prevention of other disorders.

The association between leukocytosis and increased morbidity and mortality of ischemic vascular disease has been observed for more than half a century, and recent studies in >350 000 patients confirm the robustness of the association and the dramatically higher relative and absolute acute and chronic mortality rates in patients with high versus low leukocyte counts. Although there is reason to believe that the association is not causal (that is, that leukocytosis is simply a marker of inflammation), there is also reason to believe that the leukocytosis directly enhances acute thrombosis and chronic atherosclerosis. Leukocytosis also is associated with poor prognosis and vaso-occlusive events in patients with sickle cell disease, and experimental data suggest a direct role for leukocytes in microvascular obstruction. The only way to test whether leukocytes contribute directly to poor outcome in ischemic cardiovascular disease is to assess the effect of modifying leukocyte function or number. Because selective blockade of leukocyte integrin αMβ2 and P-selectin have thus far been disappointing as therapeutic strategies in human cardiovascular and cerebrovascular disease, I discuss the potential risks and benefits of short-term treatment with hydroxyurea to decrease the leukocyte count in select populations of patients at the highest risk of short-term death.

Advances in human genome editing, in particular the development of the clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 method, have led to increasing concerns about the ethics of editing the human genome. In response, the US National Academy of Sciences and the National Academy of Medicine constituted a multidisciplinary, international committee to review the current status and make recommendations. I was a member of that committee, and the core of this review reflects the committee's conclusions. The committee's report, issued in February 2017, recommends the application of current ethical and regulatory standards for gene therapy to somatic (nonheritable) human genome editing. It also recommends allowing experimental germline genome editing to proceed if ( a) it is restricted to preventing transmission of a serious disease or condition, ( b) the edit is a modification to a common DNA sequence known not to be associated with disease, and ( c) the research is conducted under a stringent set of ethical and regulatory requirements. Crossing the so-called red line of germline genome editing raises important bioethical issues, most importantly, serious concern about the potential negative impact on individuals with disabilities. This review highlights some of the major ethical considerations in human genome editing in light of the report's recommendations.

An integrin found on platelets, α_IIbβ₃ mediates platelet aggregation, and α_IIbβ₃ antagonists are effective antithrombotic agents in the clinic. Ligands bind to integrins in part by coordinating a magnesium ion (Mg²⁺) located in the β subunit metal ion–dependent adhesion site (MIDAS). Drugs patterned on the integrin ligand sequence Arg-Gly-Asp have a basic moiety that binds the α_IIb subunit and a carboxyl group that coordinates the MIDAS Mg²⁺ in the β₃ subunits. They induce conformational changes in the β₃ subunit that may have negative consequences such as exposing previously hidden epitopes and inducing the active conformation of the receptor. We recently reported an inhibitor of α_IIbβ₃ (RUC-1) that binds exclusively to the α_IIb subunit; here, we report the structure-based design and synthesis of RUC-2, a RUC-1 derivative with a ~100-fold higher affinity. RUC-2 does not induce major conformational changes in β₃ as judged by monoclonal antibody binding, light scattering, gel chromatography, electron microscopy, and a receptor priming assay. X-ray crystallography of the RUC-2–α_IIbβ₃ headpiece complex in 1 mM calcium ion (Ca²⁺)/5 mM Mg²⁺ at 2.6 Å revealed that RUC-2 binds to α_IIb the way RUC-1 does, but in addition, it binds to the β₃ MIDAS residue glutamic acid 220, thus displacing Mg²⁺ from the MIDAS. When the Mg²⁺ concentration was increased to 20 mM, however, Mg²⁺ was identified in the MIDAS and RUC-2 was absent. RUC-2’s ability to inhibit ligand binding and platelet aggregation was diminished by increasing the Mg²⁺ concentration. Thus, RUC-2 inhibits ligand binding by a mechanism different from that of all other α_IIbβ₃ antagonists and may offer advantages as a therapeutic agent.

Objective—: Treatment of myocardial infarction within the first 1 to 2 hours with a thrombolytic agent, percutaneous coronary intervention, or an αIIbβ3 antagonist decreases mortality and the later development of heart failure. We previously reported on a novel small molecule αIIbβ3 antagonist, RUC-2, that has a unique mechanism of action. We have now developed a more potent and more soluble congener of RUC-2, RUC-4, designed to be easily administered intramuscularly by autoinjector to facilitate its use in the prehospital setting. Here, we report the properties of RUC-4 and the antiplatelet and antithrombotic effects of RUC-2 and RUC-4 in animal models. Approach and Results—: RUC-4 was ≈20% more potent than RUC-2 in inhibiting human ADP-induced platelet aggregation and much more soluble in aqueous solutions (60–80 mg/mL). It shared RUC-2’s specificity for αIIbβ3 versus αVβ3, did not prime the receptor to bind fibrinogen, or induce changes in β3 identified by a conformation-specific monoclonal antibody. Both RUC-2 and RUC-4 prevented FeCl ₃ -induced thrombotic occlusion of the carotid artery in mice and decreased microvascular thrombi in response to laser injury produced by human platelets infused into transgenic mice containing a mutated von Willebrand factor that reacts with human but not mouse platelets. Intramuscular injection of RUC-4 in nonhuman primates at 1.9 and 3.85 mg/kg led to complete inhibition of platelet aggregation within 15 minutes, with dose-dependent return of platelet aggregation after 4.5 to 24 hours. Conclusions—: RUC-4 has favorable biochemical, pharmacokinetic, pharmacodynamic, antithrombotic, and solubility properties as a prehospital therapy of myocardial infarction, but the possibility of increased bleeding with therapeutic doses remains to be evaluated.

In an attempt to help investigators judge the likelihood that a translational project will be successful, we propose a series of questions that form a self-guided global risk assessment tool.