Chapter 177

## Abstract

1. Human platelets participate in a number of adhesive events that are crucial for repair of the vasculature. Although lacking in protein synthetic capability, platelets come equipped with a variety of membrane receptors and intracellular organelles that make them highly efficient “adhesion machines” for mediating the primary hemostatic process. Adhesion itself is an activating event, and it results in the transmission of signals to the cell interior by virtue of cell-surface receptors that form cytoplasmic connections with intracellular kinases, G proteins, and cytoskeletal components. Platelet activation, in turn, elicits the secretion of several types of intracellular granules, the contents of which serve to embellish further the formation of the platelet plug by providing additional adhesive ligands that can add to the local concentration of intercellular glue molecules.

2. The αIIbβ3 integrin receptor (also called glycoprotein [GP] IIb-IIIa) is the most abundant receptor on the platelet surface, representing nearly 15 percent of total surface protein. Glanzmann thrombasthenia is a rare, inherited, autosomal recessive bleeding disorder, the hallmark of which is the failure of platelets to bind fibrinogen and aggregate following stimulation by physiological agonists such as ADP, thrombin, epinephrine, or collagen. Underlying this disorder are abnormalities of either the αIIb or β3 gene. Glanzmann thrombasthenia is characterized by significant mucocutaneous bleeding beginning at an early age. Nearly 200 individuals with Glanzmann thrombasthenia have been described in the literature and 75 molecular defects have been identified in 61 kindreds. The molecular abnormalities have ranged from major deletions and inversions easily detectable by Southern blot analysis to single point mutations identified only by nucleotide sequence analysis of the genome or platelet mRNA-derived PCR products.

3. The GPIb complex is crucial for initial attachment and proper adhesion to the extracellular matrix of a damaged vessel. Bernard-Soulier syndrome represents the second most recognized inherited platelet disorder, and is characterized by a prolonged bleeding time, giant platelets, normal platelet aggregation with ADP, collagen, and epinephrine, but absent platelet agglutination in the presence of ristocetin. The Bernard-Soulier syndrome is an autosomal recessive disorder in which most patients have a decrease to absence of all four members of the GPIb complex, each encoded by a separate gene: GPIbα, GPIbβ, GPIX, and GPV. These genes have been cloned and characterized, and a growing number of patients have had the responsible defect defined on a molecular level. Defects in the GPIb complex are also responsible for another bleeding disorder—platelet-type (or pseudo-) von Willebrand disease—in which the platelet receptor exhibits increased affinity for von Willebrand factor (VWF).

4. In addition to amino acid changes that disrupt function and result in bleeding diatheses, several platelet membrane glycoproteins have naturally occurring allelic forms within the human gene pool. Two clinically recognized immunologic syndromes are attributable to “platelet-specific” polymorphisms. Neonatal alloimmune thrombocytopenia is characterized by neonatal thrombocytopenia due to passively transmitted maternal antibodies directed against a platelet antigen inherited from the father and lacking on maternal platelets. Posttransfusion purpura is quite rare, and is characterized by acute, usually severe, thrombocytopenia 7 to 10 days after a blood transfusion. As the precise nucleotide sequence polymorphisms associated with the major human platelet alloantigen systems have become defined, it has become possible to develop and apply DNA-based diagnostic tests.

5. Human platelets contain several different types of intracytoplasmic granules that can be distinguished by electron microscopy, including α-granules, dense (or δ-) granules, and lysosomes. These granules play a major role in platelet plug formation following platelet activation. Patients with defects in the platelet-dense granules have a storage pool deficiency. The two most common platelet storage pool disorders are known as Hermansky-Pudlak syndrome and Chediak-Higashi syndrome, and the genes involved in these diseases have been cloned. A number of patients have been described who have a deficiency in α-granules, a disorder known as the gray platelet syndrome. These platelets are markedly deficient in α-granule-specific proteins such as platelet factor 4, β-thromboglobulin, VWF, factor V, fibronectin, and platelet-derived growth factor.

6. Following the binding of an agonist to its platelet receptor, a signal is transferred across the cell membrane into the cell either directly by the membrane receptor or through intervening Gαβδ heterotrimeric proteins. Signal transduction results in secondary changes within the platelet that include ionic calcium fluxes, cAMP formation, phospholipase A2 and C activation, changes in arachidonate pathway metabolism, protein kinase C activation, and protein phosphorylation. Patients with inherited disorders of platelet signal transduction have been described. The most prominent of these has been the Wiskott-Aldrich syndrome (WAS) that affects both platelets and lymphocytes.

7. Activated platelets play a role in accelerating the proteolytic events that take place as part of the coagulation cascade, and this property has been termed “platelet factor 3 activity.” The procoagulant properties have been attributed to a number of characteristics unique to the surface of activated platelets, including exposure of phosphatidylserine moieties, redistribution of specific receptors for factors V and X, and development of platelet microvesicles. One of the best-characterized inherited disorders of platelet factor 3 activity is known as Scott syndrome. The defect in this disorder is not limited to platelet membranes, as erythrocytes from patients with Scott syndrome also have decreased microvesiculation and fewer factor Va binding sites than normal following A23187 ionophore stimulation. The molecular basis of any of these disorders has yet to be determined.

8. The process by which platelet formation occurs is a fascinating one. Megakaryocytopoiesis begins with the self-renewing hematopoietic stem cell in the bone marrow that becomes progressively committed to the megakaryoblast lineage, eventually resulting in the production of a mature megakaryocyte that “terminally differentiates” by releasing a shower of ~104 platelets. The size variation and heterogeneity in platelets seen in various disease states may be related to cytoskeletal problems or to the site and mechanism of formation. A number of the inherited platelet disorders involve abnormal platelet size, including the macrothrombocytopenic states seen in Bernard-Soulier syndrome and the May-Hegglin anomaly, as well as the microthrombocytopenia seen in WAS. Decreased platelet counts also occur and involve the above three disorders as well as the recently recognized family platelet deficiency/acute myelogenous leukemia (FPD/AML) syndrome.

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