Molecular Mechanisms in Platelet Disorders

This issue of Seminars in Thrombosis and Hemostasis is the second of two companion issues focusing on platelets, and it delves into the molecular mechanisms of diseases associated with altered platelets.

The present issue starts with a succinct review on the power of a technology, flow cytometry, which has contributed in a major way to the assessment of platelet biology and the alterations in disease. The applicability and versatility of this tool to assess the manifold aspects of platelets are impressive and expanding. Written by Michelson and his colleagues, this review captures the state-of-the-art technology.

The last few years have seen major advances in the unraveling of some of the molecular genetic defects in patients with inherited thrombocytopenias. One of them is the delineation of mutations in the nonmuscle myosin heavy chain gene (MYH9) in a diverse group of patients who have previously carried different eponyms. Balduini and Savoia discuss these and other entities associated with inherited thrombocytopenias, including mutations in transcription factors (GATA-1, AML-1/CBFA2) and other genes. The end result is a comprehensive review of the various genetic abnormalities that present with a decreased platelet count on an inherited basis.

The next review deals with the area of inherited defects in platelet function. Despite the rapid progress in our understanding of the biochemical mechanisms operating in normal platelets, our knowledge of the molecular and genetic mechanisms in the vast majority of patients who have an inherited defect in platelet function remains incomplete. Most of them do not have the commonly considered defects, such as the membrane glycoprotein deficiencies or the storage pool deficiency. There is burgeoning evidence that defects in platelet signal transduction mechanisms may underlie the impairment in the end responses to activation, such as aggregation and dense granule release. Rao, Jalagadugula, and Sun present an overview of this area.

The next review by Gahl and colleagues focuses on the disorders that arise from aberrations in the platelet dense granule. What emerges is a major theme in which confluence of detailed insights from specific disorders in man (such as the storage pool deficiency and the Hermansky-Pudlak syndrome) and elegant animal models produce paradigms to understand fundamental aspects of formation and behavior of granules-not only in platelets but also melanosomes in melanocytes and vesicles in other cells. This review brings out both the clinical aspects and the exciting genetic defects associated with dense granule disorders.

Thrombotic thrombocytopenic purpura (TTP) has been recognized for several decades, but it is only recently that its molecular basis has been unraveled to a deficiency of a von Willebrand factor-cleaving protease (ADAMTS13) activity in plasma. The demonstration that most patients with TTP have antibodies that inhibit ADAMTS13 and the identification of specific mutations in the hereditary forms of TTP have been exciting recent advances. In his review on TTP, Tsai describes the molecular mechanisms and the clinical aspects of TTP.

The next review deals with the entities of heparin-induced thrombocytopenia (HIT) and idiopathic thrombocytopenic purpura, which are two distinct diseases, linked because of an immune basis of both disorders. The development of elegant mouse models to explore the immune mechanisms in these entities, especially for HIT, have advanced our understanding of their basic pathophysiology and provided answers to fundamental questions about the inciting mechanisms. McKenzie and Reilly describe the molecular events and the important insights gained from the mouse models.

Agents that block the GPIIb/IIIa complexes on platelets are widely used in patients with acute coronary syndromes. These have come with the unwanted baggage of thrombocytopenia, occasionally acute and dramatic within hours of initiation. It is now becoming clear that these are mediated by drug-dependent antibodies in most cases, and that the antibodies may be present even in unexposed individuals. Aster, Curtis, and Bougie describe the current understanding of the molecular mechanisms involved and discuss a clinical approach to individuals with thrombocytopenia following exposure to this class of potent antiplatelet agents.

It has been known for a long time that a hemostatic defect accompanies patients with renal failure and that this is largely a platelet phenomenon. In the next review, Boccardo, Remuzzi, and Galbusera present a lucid overview of the platelet dysfunction in renal failure, with a focus on the recent advances in our knowledge of the alterations in platelet biochemical mechanisms and platelet-vessel wall interactions, including on the modulating role of nitric oxide and prostacyclin.

Platelet glycoproteins GPIb-IX-V, GPIIb-IIIa, and GPIa-IIa all play critical roles in platelet interactions with the vessel wall and with each other in hemostasis and thrombosis. An area that has recently received substantial attention is the impact of genetic polymorphisms in these proteins on platelet biology and on the potential clinical importance. These issues are reviewed by Yee and Bray and constitute what may become a strong basis for evidence-based applications of pharmacogenetics in the large numbers of patients with atherothrombotic disease.

In all, the reviews that comprise this issue deliver a capsule of the recent advances in platelet biology and the aberrations in disease. They are from individuals who have contributed to the current body of knowledge. My thanks to all of the authors who have contributed to this issue and to Mrs. Mary Merrick for her assistance all the way.