Three world-renowned speakers – Alan Nurden of France, Marco Cattaneo of Italy, and Barry Coller of the Unites States – came together Monday to present the state of the art regarding platelet function and dysfunction during a session named for 1981 ISTH Congress President  J. Fraser Mustard, who was a pioneer in the area of platelet research.

Inherited Disorders of Platelet Function

From left, Marco Cattaneo, Alan Nurden, and Barry Coller

From left, Marco Cattaneo, Alan Nurden, and Barry Coller

Nurden, of Hôpital Xavier Arnozan, Pessac, focused on inherited disorders of platelet function, describing the gene variants responsible for the primary genotype of many platelet disorders. He also discussed how next-generation sequencing technology has identified genes responsible for defects in platelet secretion, procoagulant activity, and activation pathways, as well as how it has furthered our understanding of the mechanisms of platelet production and function.

Regarding his own work on the international Genoscope study comparing the genotype and phenotype of cases in 76 families affected by Glanzmann thrombasthenia (GT – the “classic inherited platelet disorder”), he said the findings allowed for enlargement of the mutation spectrum in GT.

Most families have mutations and gene variants that may prevent protein synthesis, abrogate function, or result in aberrant activation proteins, but bleeding severity is difficult to predict by genotype alone, he said, noting that this suggests other factors are at play.

Nurden concluded that the most important challenge today is to identify those factors and help improve patient care.

“Let’s help the patient know if he is more likely to have an angiodysplasia. Let’s help the patient know if he’s more likely to bleed more than another member of the family, and that will be because he has something else – or many other things – in the genome, that we need to identify,” he said.

Structure and Function of P2Y12 ADP Receptor

Cattaneo, of Universita degli Studi di Milano, discussed the structure and function of the platelet P2Y12 receptor (P2Y12R) for adenosine 5’- diphosphate (ADP), which plays a central role in platelet function, hemostasis and thrombosis.

He described the roles of P2Y12R in inflammation as well as the drugs that inhibit P2Y12R. The most widely used of these drugs is clopidogrel, but that drug has an important drawback – its inability to adequately inhibit P2Y12R-dependent platelet function in about a third of patients.

New drugs, including prasugrel and ticagrelor, are proving more efficacious in preventing major adverse cardiovascular events through their effective inhibition of P2Y12R, he said.

“P2Y12R for ADP plays a key role in the formation of the hemostatic plug and the pathogenesis of arterial thrombi. It is defective in some patients with a congenital bleeding diathesis and is an established target for antithrombotic drugs,” he said, adding that experimental studies have indicated that antagonism of P2Y12R modulates inflammation and decreases tumor growth and metastasis.

αIIbβ3 Structure and Function

Coller, of Rockefeller University, New York, focused on the structure and function of the platelet integrin αIIbβ3, with a particular focus on nanodisc technology-enabled advances in imaging intact αIIbβ3 in a lipid bilayer in the absence of detergent, and on new structural insights into the changes in the ligand-binding pocket with receptor activation and ligand binding.

He also described limitations of existing αIIbβ3 antagonists (such as a risk of thrombocytopenia in a small percentage of patients) and novel therapeutic αIIbβ3 antagonists currently in development, including the small molecule antagonist Ur-3216/2922, activation-specific single-chain antibodies, and the RUC compounds. RUC-4, the latest of these compounds, is a much more water soluble derivative of RUC-2 that shows very similar binding and antithrombotic properties. It is currently in development for the pre-hospital therapy of ST segment elevated myocardial infarction.

Nurden reported having no disclosures. Cattaneo reported receiving grants and personal fees from Eli Lily, Daiichi Sankyo, AstraZeneca, and The Medicine Company. Coller was supported in part by grants from the NHLBI, the National Center for Advancing Translational Science, and from Stony Brook University. Coller also disclosed royalty interests in abciximab (Centocor) and the VerifyNow assays (Accumetrics).

By Sharon Worcester |June 22, 2015