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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:285.)
© 2000 American Heart Association, Inc.

Brief Reviews

Congenital Disorders of Platelet Signal Transduction

A. Koneti Rao; Jagadeesh Gabbeta

From the Department of Medicine and the Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pa.

Key Words: congenital platelet function disorders • signal transduction defects • disorders of secretion

	Introduction

Top Introduction Congenital Disorders of Platelet... Disorders of Platelet Secretion... Deficiency of Granule Stores Defects in Platelet Signal... Signal Transduction Defects and... Abnormalities in Arachidonic... Defects in Cytoskeletal Assembly Relative Frequencies and Therapy... Conclusions References

 
After injury to the blood vessel, platelets adhere to the exposed subendothelium by a process (adhesion) that involves the interaction of a plasma protein, von Willebrand factor (vWF), and a specific protein on the platelet surface, glycoprotein Ib (GPIb; the Figure). Adhesion is followed by recruitment of additional platelets that form clumps, a process called aggregation (cohesion). This involves binding of fibrinogen to specific platelet surface receptors—a complex comprising glycoproteins IIb-IIIa (GPIIb-IIIa). Activated platelets release the contents of their granules (secretion or release reaction), such as ADP and serotonin from dense granules, which subsequently cause recruitment of additional platelets. In addition, platelets play a major role in coagulation mechanisms; several key enzymatic reactions occur on the platelet membrane–lipoprotein surface. A number of physiological agonists interact with specific receptors on the platelet surface to induce responses, including a change in platelet shape from discoid to spherical, aggregation, secretion, and thromboxane A₂ (TxA₂) production. Other agonists such as prostacyclin inhibit these responses. Ligation of the platelet receptors initiates the production or release of several intracellular messenger molecules, including Ca²⁺ ions, products of phosphoinositide (PI) hydrolysis by phospholipase C (PLC; diacylglycerol [DG] and inositol 1,4,5-triphosphate [InsP₃]), TxA₂, and cyclic nucleotides (cAMP; the Figure). These subsequently induce or modulate the various platelet responses of Ca²⁺ mobilization, protein phosphorylation, aggregation, secretion, and liberation of arachidonic acid. The interaction between the agonist receptors and the key intracellular effector enzymes (eg, PLA₂, PLC, adenylyl cyclase) is mediated by a group of GTP-binding proteins that are modulated by GTP. As in most secretory cells, platelet activation results in a rise in cytoplasmic ionized calcium concentration; InsP₃ functions as a messenger to mobilize Ca²⁺ from intracellular stores. DG activates protein kinase C (PKC), and this results in the phosphorylation of the 47-kDa protein pleckstrin. PKC activation is considered to play a major role in platelet secretion and in the activation of GP IIb-IIIa. Numerous other mechanisms, such as phosphorylation of proteins by nonreceptor tyrosine kinases, also play a role in signal transduction. A detailed description of the platelet activation mechanisms is beyond the scope of this review. Inherited or acquired defects in the above platelet mechanisms may lead to an impaired platelet role in hemostasis.

View larger version (52K): [in this window] [in a new window]   Figure 1. Schematic representation of normal platelet responses and the congenital disorders of platelet function. Some of the platelet-mediated coagulation protein interactions are also shown. Coagulation proteins are shown by Roman numerals, with the activated forms designated by the letter a. The arrows designate conversions of zymogens to enzymes. CO indicates cyclooxygenase; DAG, diacylglycerol; G, GTP-binding protein; IP3, inositol trisphosphate; MLC, myosin light chain; MLCK, myosin light-chain kinase; PIP2, phosphatidylinositol bisphosphate; PKC, protein kinase C; PLC, phospholipase C; PLA2, phospholipase A2; R, receptor; TK, tyrosine kinase; and TS, thromboxane synthase. Other abbreviations are defined in text.

	Congenital Disorders of Platelet Function

Top Introduction Congenital Disorders of Platelet... Disorders of Platelet Secretion... Deficiency of Granule Stores Defects in Platelet Signal... Signal Transduction Defects and... Abnormalities in Arachidonic... Defects in Cytoskeletal Assembly Relative Frequencies and Therapy... Conclusions References

 
Disorders of platelet function are characterized by highly variable mucocutaneous bleeding manifestations and excessive hemorrhage after surgical procedures or trauma. A majority of patients, but not all, have a prolonged bleeding time. Platelet aggregation and secretion studies provide evidence for the defect but are not always predictive of the severity of clinical manifestations. The platelet dysfunction in these patients arises by diverse mechanisms.^{1 2 3} The Table 1 provides a classification based on the platelet functions or responses that are abnormal (the Figure). In patients with defects in platelet–vessel wall interactions, adhesion of platelets to the subendothelium is abnormal. The 2 disorders in this group are von Willebrand disease (vWD), due to a deficiency or abnormality in plasma vWF,⁴ and the Bernard-Soulier syndrome, in which platelets are deficient in GPIb (and GPV and IX), and the binding of vWF to platelets is abnormal.⁵ Disorders characterized by abnormal platelet-platelet interactions (aggregation) arise because of a severe deficiency of plasma fibrinogen (congenital afibrinogenemia) or because of a quantitative or qualitative abnormality of the platelet membrane GPIIb-IIIa complex (Glanzmann thrombasthenia).⁶ Patients with defects in platelet secretion and signal transduction are a heterogeneous group, lumped together for convenience of classification rather than on the basis of an understanding of the specific underlying abnormality. The major common characteristic in these patients, as currently perceived, is an inability to release intracellular (dense) granule contents on activation of platelet-rich plasma with agonists such as ADP, epinephrine, and collagen. In aggregation studies, the second wave of aggregation is blunted or absent. A small proportion of these patients have a deficiency of dense granule stores (storage pool deficiency). In some of the other patients, the impaired secretion results from aberrations in the signal transduction events that govern end responses such as secretion and aggregation. This review will focus on these patients, who are encountered more often than are those with thrombasthenia or the Bernard Soulier syndrome. Last are the patients who have an abnormality in interactions of platelets with proteins of the coagulation system; the best described is the Scott syndrome.⁷ In addition to the aforementioned groups, there are patients who have abnormal platelet function associated with systemic disorders such as Down syndrome and the May-Hegglin anomaly, in which the specific aberrant platelet mechanisms are still unclear.

View this table: [in this window] [in a new window]   Table 1. Classification of Congenital Disorders of Platelet Function

	Disorders of Platelet Secretion and Signal Transduction

Top Introduction Congenital Disorders of Platelet... Disorders of Platelet Secretion... Deficiency of Granule Stores Defects in Platelet Signal... Signal Transduction Defects and... Abnormalities in Arachidonic... Defects in Cytoskeletal Assembly Relative Frequencies and Therapy... Conclusions References

 
As a unifying theme, patients lumped in this heterogeneous group generally manifest impaired secretion of granule contents and an absence of the second wave of aggregation on stimulation of platelet-rich plasma with ADP and epinephrine; responses to collagen, thromboxane analogue (U46619), arachidonic acid, and platelet-activating factor (PAF) may also be impaired. Platelet function is abnormal in these patients either when the granule contents are diminished (storage pool deficiency [SPD]) or when there is an aberration in the activation mechanisms governing aggregation and secretion (the Table).

	Deficiency of Granule Stores

Top Introduction Congenital Disorders of Platelet... Disorders of Platelet Secretion... Deficiency of Granule Stores Defects in Platelet Signal... Signal Transduction Defects and... Abnormalities in Arachidonic... Defects in Cytoskeletal Assembly Relative Frequencies and Therapy... Conclusions References

 
The term storage pool deficiency (SPD) refers to patients with deficiencies in platelet content of dense granules (-SPD), -granules (-SPD), or both types of granules (-SPD).^{3 8} The Quebec platelet disorder is an autosomal dominant disorder associated with abnormal proteolysis of -granule proteins, deficiency of platelet -granule multimerin (a factor V–binding protein), and markedly impaired aggregation with epinephrine as a striking feature.⁸

	Defects in Platelet Signal Transduction (Primary Secretion Defects)

Top Introduction Congenital Disorders of Platelet... Disorders of Platelet Secretion... Deficiency of Granule Stores Defects in Platelet Signal... Signal Transduction Defects and... Abnormalities in Arachidonic... Defects in Cytoskeletal Assembly Relative Frequencies and Therapy... Conclusions References

 
Signal transduction mechanisms encompass processes that are initiated by the interaction of agonists with specific platelet receptors and include responses such as G-protein activation and activation of effectors such as PLC and PLA₂. If the key components in signal transduction are the surface receptors, the G proteins, and the effectors, then evidence now exists for specific platelet abnormalities at each of these levels.

Defects in Platelet-Agonist Interaction: Receptor Defects
These patients have impaired responses because of an abnormality in the platelet surface receptor for a specific agonist. Such receptor defects have been documented for epinephrine,⁹ collagen,^{10 11 12 13} ADP,^{14 15 16} and TxA₂.^{17 18 19 20} Hirata et al¹⁷ have described an Arg 60 to Leu mutation of the human TxA₂ receptor in a dominantly inherited bleeding disorder. Patients described by Cattaneo et al^{14 16} and Nurden et al¹⁵ have a defect in the interaction of ADP with one of its receptors. Because ADP and TxA₂ play a synergistic role in platelet responses to several agonists, patients with these receptor defects manifest abnormal responses to multiple agonists. A few patients have been described in whom platelet responses to collagen only are blunted and are associated with deficiencies in membrane glycoproteins, including GPIa and GPVI.^{10 11 12 13} GPVI-deficient platelets have been reported to have impaired collagen activation of tyrosine kinase Syk but not c-Src.²¹

Defects in G-Protein Activation
G proteins are a heterogeneous group of proteins that link surface receptors and intracellular effector enzymes and constitute an important potential aberrant locus leading to platelet dysfunction. Convincing evidence for such a defect has been provided by Gabbeta et al²² in a patient with a mild bleeding disorder, abnormal aggregation and secretion responses to a number of agonists, and diminished GTPase activity (a reflection of G-protein -subunit function) on activation. This patient had a selective decrease in the platelet membrane G_q subunit but normal levels of G_i, G₁₂, G₁₃, and G_z. She has been reported to have impaired Ca²⁺ mobilization²³ and diminished release of free arachidonic acid from phospholipids on platelet activation.²⁴ Essentially identical abnormal platelet findings have been reported in the G_q-deficient knockout mouse.²⁵ Impaired G-protein activation has also been reported in patients with the TxA₂ receptor defect.^{18 19}

Defects in Phospholipase C Activation, Calcium Mobilization, Pleckstrin Phosphorylation, and Tyrosine Phosphorylation
Several patients have been identified who have a relatively mild bleeding diathesis and impaired dense granule secretion, although their platelets have normal granule stores and, in general, synthesize substantial amounts of TxA₂.^{26 27} These patients have abnormal aggregation and secretion particularly in response to weaker agonists (ADP, epinephrine, and PAF); the response to relatively stronger agonists such as arachidonate and high concentrations of collagen may be normal. Such patients are far more common than those with SPD or defects in TxA₂ synthesis. Lages and Weiss²⁶ have described 8 such patients who had decreased initial rates and extents of aggregation in response to ADP, epinephrine, and U44169. Defects in early platelet-activation events were postulated in these patients. They subsequently demonstrated in one of these patients a defect in phosphatidylinositol hydrolysis and phosphatidic acid formation,²⁸ and pleckstrin phosphorylation.²⁹

An early response to platelet stimulation is the rise in cytoplasmic Ca²⁺ concentration. Therefore, attention has been focused on this process to explain the impaired aggregation and secretion. In several patients, defects in calcium mobilization have been proposed on the basis of impaired platelet responses to the calcium ionophore A23187¹ ; however, this evidence is indirect at best. Direct evidence has been provided that some of these patients have impaired Ca²⁺ mobilization on platelet activation.^{23 30} Detailed studies in 2 patients with impaired aggregation and secretion revealed that the resting cytoplasmic Ca²⁺ concentration was normal but the peak Ca²⁺ concentrations after activation with ADP, collagen, PAF, or thrombin were diminished,³⁰ with abnormalities in both the release of Ca²⁺ from intracellular stores and the influx of extracellular Ca²⁺.²³ Further studies showed a defect in platelet formation of InsP₃ (the key intracellular mediator of Ca²⁺ release) and DG and in pleckstrin phosphorylation,³¹ indicating a defect in PLC activation. Human platelets contain at least 7 PLC isozymes in the quantitative order PLC-2>PLC-ß2>PLC-ß3>PLC-ß1>PLC-1> PLC-1>PLC-ß4.³² Studies in 1 of these patients revealed a selective deficiency in PLC-ß2 with normal levels of other PLC isoforms.³² These studies provide strong evidence that PLC-ß2, a G protein–linked PLC isozyme, plays a major physiological role in platelet responses to activation. In line with these studies, knockout mice deficient in PLC-ß2 have impaired Ca²⁺ mobilization in neutrophils.³³

Several other studies provide evidence for defects in signaling mechanisms, phosphatidylinositol metabolism, and protein phosphorylation in patients with abnormal platelet aggregation and secretion.^{28 29 34 35} Holmsen et al³⁴ described a patient with abnormal platelet aggregation and dense granule secretion who had impaired release of free arachidonic acid and phosphoinositide hydrolysis on thrombin activation. However, no studies were performed on Ca²⁺ mobilization or Ins1,4,5P₃ production, and the platelets had reduced GPIIb and IIIa as well. Another patient has been described with impaired platelet responses and diminished phosphoinositide metabolism in whom the altered stimulus-response coupling has been attributed to abnormal membrane phospholipid composition.³⁶ Fuse et al¹⁹ have reported a patient with a mild bleeding disorder whose platelets had impaired aggregation, secretion, InsP₃ formation, and Ca²⁺ mobilization in response to a TxA₂ mimetic (STA₂) associated with normal TxA₂ formation. Interestingly, GTPase activity on activation with STA₂ was also impaired, leading to the conclusion that the platelets had an abnormality in coupling between the TxA₂ receptor and PLC. In the patient described by Mitsui,³⁵ the abnormal platelet aggregation was associated with decreased TxA₂-induced InsP₃ formation but with normal TxA₂ receptors and GTPase activity on stimulation with TxA₂ analogue U46619, suggesting an abnormality in PLC activity downstream from the receptor. In an analysis of 5 patients with absent TxA₂-induced aggregation, Fuse et al²⁰ found evidence for a receptor defect in 3 patients; in the other 2, the primary abnormality appeared distal to the receptor. Together the above studies provide evidence for abnormalities in signal transduction pathways in patients with diminished platelet aggregation and secretion responses.

Yang et al²⁷ have summarized detailed studies on signaling mechanisms in 8 patients with abnormal aggregation and secretion in response to several different surface receptor–mediated agonists despite the presence of normal dense granule contents. Both PKC-induced pleckstrin phosphorylation and cytoplasmic Ca²⁺ mobilization play a major role in aggregation/secretion on activation. Receptor-mediated Ca²⁺ mobilization and/or pleckstrin phosphorylation was abnormal in 7 of the patients. It was postulated that combined platelet activation with a cell-permeable direct PKC activator, 1,2-dioctanoyl-sn-glycerol, and ionophore A23187, which possibly bypasses 2 major intracellular mediators (InsP₃ and DG), may induce normal dense granule secretion in patients with impaired receptor-mediated secretion. Platelet activation with a combination of ADP and either 1,2-dioctanoyl-sn-glycerol or A23187 improved secretion in 4 patients. However, a combination of 1,2-dioctanoyl-sn-glycerol and A23187 induced normal secretion in platelet-rich plasma in all patients, suggesting that the ultimate process of exocytosis or secretion per se is intact and that impaired secretion in these patients results from abnormalities in early signal transduction events.

There is growing evidence that protein phosphorylation by tyrosine kinases (members of the Src-kinase family, the focal adhesion kinase [FAK] family, pp72^syk, and the Janus [JAK] kinase family) plays an important role in platelet signal transduction.³⁷ In thrombasthenia^{38 39} and the Scott syndrome,⁴⁰ tyrosine phosphorylation of several proteins is impaired on platelet activation. In these disorders, this defect is a result of the primary abnormality in the GPIIb-IIIa complex and in phospholipid scrambling, respectively.^{37 39 40}

	Signal Transduction Defects and Activation of GPIIb-IIIa Complex

Top Introduction Congenital Disorders of Platelet... Disorders of Platelet Secretion... Deficiency of Granule Stores Defects in Platelet Signal... Signal Transduction Defects and... Abnormalities in Arachidonic... Defects in Cytoskeletal Assembly Relative Frequencies and Therapy... Conclusions References

 
Activation of GPIIb-IIIa and platelet fibrinogen binding, a prerequisite for aggregation, is a signal transduction–dependent process and has been linked to PKC activation. Therefore, it is likely that abnormalities in signaling mechanisms may impair the activation of GPIIb-IIIa on platelets. Evidence that this is indeed the case is provided by the decreased activation of otherwise normal platelet GPIIb-IIIa complexes in a patient with markedly abnormal platelet aggregation and impaired pleckstrin phosphorylation.⁴¹ The number and ligand-binding capacity of the GPIIb-IIIa complex were intact. A similar abnormality in GPIIb-IIIa activation has been observed in platelets with the G_q deficiency,²² attesting to the role of G_q in GPIIb-IIIa activation. Moreover, the defect in GPIIb-IIIa activation provides a cogent explanation for abnormalities in initial aggregation responses noted by Lages and Weiss²⁶ in a number of their patients. Diminished activation of GPIIb-IIIa secondary to upstream signal transduction defects may be a more common mechanism than defects in the GPIIb-IIIa complex per se in patients with blunted aggregation.²²

	Abnormalities in Arachidonic Acid Pathways and Thromboxane Production

Top Introduction Congenital Disorders of Platelet... Disorders of Platelet Secretion... Deficiency of Granule Stores Defects in Platelet Signal... Signal Transduction Defects and... Abnormalities in Arachidonic... Defects in Cytoskeletal Assembly Relative Frequencies and Therapy... Conclusions References

 
A major platelet response to activation is liberation of arachidonic acid from phospholipids and its subsequent oxygenation to TxA₂. TxA₂ production plays a synergistic role in the response to several agonists. Patients have been described with impaired liberation of arachidonic acid from membrane phospholipids during platelet stimulation.^{22 24 34} Several patients have been described with platelet dysfunction associated with congenital deficiencies of cyclooxygenase and thromboxane synthase.¹

	Defects in Cytoskeletal Assembly

Top Introduction Congenital Disorders of Platelet... Disorders of Platelet Secretion... Deficiency of Granule Stores Defects in Platelet Signal... Signal Transduction Defects and... Abnormalities in Arachidonic... Defects in Cytoskeletal Assembly Relative Frequencies and Therapy... Conclusions References

 
The Wiskott-Aldrich syndrome (WAS) is an X-linked inherited disorder affecting T lymphocytes and platelets and characterized by thrombocytopenia, immunodeficiency, and eczema.⁴² Several platelet abnormalities, including dense granule deficiency, have been reported in WAS. WAS arises from mutations in the gene coding for a novel protein of 502 amino acids that binds to several other signaling proteins, including Cdc42 (a GTPase) and p47nck (a Src homology 3 domain containing adapter protein).^{42 43} This protein constitutes a link between the cytoskeleton and signaling pathways and is a key regulator of cytoskeletal assembly.⁴³

	Relative Frequencies and Therapy of Various Platelet Abnormalities

Top Introduction Congenital Disorders of Platelet... Disorders of Platelet Secretion... Deficiency of Granule Stores Defects in Platelet Signal... Signal Transduction Defects and... Abnormalities in Arachidonic... Defects in Cytoskeletal Assembly Relative Frequencies and Therapy... Conclusions References

 
Thrombasthenia and the Bernard-Soulier syndrome are rare disorders. Although there are no published data, patients currently classified in the heterogenous category of defects in platelet secretion and signal transduction probably constitute the most frequently encountered inherited platelet function abnormalities, excluding vWD. In our experience, the SPD is present in <10% to 15% of patients with congenital platelet defects. Abnormalities in thromboxane production occur in 20% of patients. A large proportion of the remaining patients with abnormal aggregation and secretion demonstrate adequate dense granule stores and produce substantial amounts of TxA₂. In some of these patients, there is evidence for defects in the signaling mechanisms. In this heterogeneous group, the underlying mechanisms still need to be established. Platelet transfusions have been the major therapeutic modality to manage bleeding in patients with intrinsic platelet defects, and this approach needs to be individualized. A viable alternative is intravenous administration of desmopressin or 1-desamino-8-D-arginine vasopressin (DDAVP), which shortens the bleeding time in a number of patients, particularly those with normal dense granule stores.^{44 45} This response is dependent on the underlying mechanism leading to the platelet dysfunction.^{44 45}

	Conclusions

Top Introduction Congenital Disorders of Platelet... Disorders of Platelet Secretion... Deficiency of Granule Stores Defects in Platelet Signal... Signal Transduction Defects and... Abnormalities in Arachidonic... Defects in Cytoskeletal Assembly Relative Frequencies and Therapy... Conclusions References

 
There has been a tremendous advance in our understanding of the role of platelets in hemostasis, and part of this has resulted from characterization of the experiments of nature, such as patients with platelet function disorders. In the vast majority of patients with inherited platelet dysfunction, the underlying mechanisms remain unknown. A better delineation of the involved platelet mechanisms is required and will translate into development of novel therapeutic strategies for a diverse group of disorders—hemorrhagic, thrombotic, atherosclerotic, and proliferative—in which platelets are involved.

	Acknowledgments

 
This work was supported by grant HL 056724 from the National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, Md.

	Footnotes

 
Reprint requests to A. Koneti Rao, MD, Division of Hematology and Thromboembolic Diseases, Temple University Health Sciences Center, Room 300 OMS, 3400 N Broad St, Philadelphia, PA 19140.

Received April 8, 1999; accepted July 14, 1999.

	References

Top Introduction Congenital Disorders of Platelet... Disorders of Platelet Secretion... Deficiency of Granule Stores Defects in Platelet Signal... Signal Transduction Defects and... Abnormalities in Arachidonic... Defects in Cytoskeletal Assembly Relative Frequencies and Therapy... Conclusions References

 

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