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Buenos Aires 01 de Febrero del 2021

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Platelet Function - Disorders 

                                                                            Anjali A. Sharathkumar; Amy Shap
                                                                       
 Indiana Hemophilia and Thrombosis Center 

                                                                          T R E A T M E N T O F  H E M O P H I L I A 
                                                            Published by the World Federation of Hemophilia (WFH), 1999

 

 

Platelets play a crucial role in hemostasis.
Platelet dysfunction due to congenital and acquired etiologies is one of the most common causes of bleeding encountered in clinical practice. Bleeding manifestations are characterized by mucocutaneous bleeding like bruising, nose bleeding, and menorrhagia, and bleeding after hemostatic stress, such as after tonsillectomy and adenoidectomy, dental extraction, and, rarely, post-partum
Clinical bleeding results from a disturbance in hemostasis. The term hemostasis applies to a myriad of physiological processes that are involved in maintaining vascular integrity and keeping the blood in fluid form.
Normal hemostasis involves interaction between three forces first described by German pathologist Rudolf Virchow in 1856: blood (with soluble and cellular components), the blood vessel, and blood flow.
Human platelets are multifunctional anucleated cells that play a vital role in hemostasis.

 Platelet Structure and Function

 Platelets originate from the cytoplasm of bone marrow megakaryocytes . Platelets lack genomic DNA but contain megakaryocytederived messenger RNA (mRNA) and the translational machinery needed for protein synthesis. Circulating platelets are discoid in shape, with dimensions of approximately 2.0-4.0 by 0.5 μm, and a mean volume of 7-11 fl. Their shape and small size enables the platelets to be pushed to the edge of vessels, placing them in the optimum location to constantly survey the integrity of the vasculature. Platelets circulate in a concentration of 150,000-450,000 cells/mL. Of the total body platelets, about 70% stay in circulation while the remaining 30% are continually but transiently sequestered in the spleen. Platelets remain in circulation for an average of 10 days. Most platelets are removed from the circulation by the spleen and liver after senescence, but a constant small fraction is continually removed through involvement in maintenance of vascular integrity
On peripheral blood smears stained with Wright-Giemsa stain, platelets appear as small, granular staining cells with a rough membrane, and are normally present as 3-10 platelets per high-power oil-immersion field. Despite their simple appearance on the peripheral blood smear, platelets have a complex structure
Platelet internal structure has been divided into four zones:

 ï‚•ï€ Peripheral zone

Sol-gel zone

Organelle zone

Membrane zone

The peripheral zone includes the outer membranes and closely associated structures.
The platelet has a surface-connected system of channels called the open canalicular system (OCS). The walls of the OCS are included in this zone. The OCS provides access to the interior of the platelet to plasma substances, and an outlet channel for platelet products. The release of platelet products through the OCS after platelet activation is called "the release reaction."
The membranes of the platelet are rich in platelet receptors, which determine its specific cellular identity. These receptors are constitutively expressed on the platelets and require conformational change during platelet activation to express receptor function.
The peripheral zone also includes membrane phospholipids. Phospholipids are an important component of coagulation as they provide the surface upon which coagulation proteins react. Phospholipids also serve as the initial substrate for platelet enzymatic reactions to produce thomboxane A2 (TXA2), an important product of platelet activation and a powerful platelet agonist (substance that causes platelet aggregation). The platelet membrane also has the ability to translate signals from the surface into internal chemical signals.
The sol-gel zone is beneath the peripheral zone and consists of the framework of the platelet, the cytoskeleton. The cytoskeleton forms the support for the maintenance of the platelet's discoid shape as well as the contractile system that allows, upon activation, shape change, pseudopod extension, internal contraction, and release of granular constituents. The cytoskeleton comprises somewhere between 30-50% of the total platelet protein.
The organelle zone consists of the granules and cellular components such as lysosomes, mitochondria, etc. These organelles serve in the metabolic processes of the platelet and store enzymes and a large variety of other substances critical to platelet function. There are two compartments of adenine nucleotides: the storage or secretable pool in dense granules and the metabolic or cytoplasmic pool. Included inthis zone are the alpha and dense granules. The dense granules contain non-metabolic adenosine triphosphate (ATP) and adenosine diphosphate (ADP), serotonin, and calcium. The alpha granules contain adhesive proteins such as fibrinogen, fibronectin, von Willebrand factor (VWF), thrombospondin, and vitronectin. The alpha granules also contain growth-promoting substances such as platelet-derived growth factor (PDGF), platelet factor 4, and transforming growth factor. Coagulation factors including factor V, high molecular weight kininogen, factor XI, and plasminogen activator inhibitor-1 are also present in the alpha granule.
The fourth zone is the membrane zone, which includes the dense tubular system. It is here that calcium, important for triggering contráctiles events, is concentrated. This zone also contains the enzymatic systems for prostaglandina synthesis.

 Role of Platelets in Hemostasis

 In a normal physiological state, platelets circulate without adhering to undisturbed vascular endothelium. Upon disruption of the integrity of the vascular endothelium or alteration in the shear stress of the blood flow, platelets are "activated." Platelet activation plays a central role in both benign and pathological responses to vascular injury and thrombus formation. The process of transformation of inactivated platelets into a well-formed platelet plug occurs along a continuum, but may be divided into three steps: (1) adhesion; (2) aggregation; and (3) secretion.

Platelet adhesion

Subendothelial components (e.g., collagen, VWF, fibronectin, and laminin) are exposedupon vessel wall damage. VWF facilitates the initial adhesion via binding to the glycoprotein (GP) Ib/IX/V complex, especially under high shear conditions. These interactions enable platelets to slow down sufficiently so that further binding interactions take place with other receptor-ligand pairs, resulting in static adhesion. In particular, the initial interaction between collagen and GPVI induces a conformational change (activation) in the platelet integrins GPIIb/IIIa and GPIa/IIa. VWF and collagen form strong bonds with GPIIb/IIIa and GPIa/IIa, respectively, anchoring the platelets in place. Recruitment of additional platelets occurs through platelet-platelet interaction that is mainly mediated through fibrinogen and its receptor, GPIIb/IIIa
Patients with Bernard-Soulier syndrome and Glanzmann's thrombasthenia have defective platelet adhesion due to decreased or absent expression of the glycoprotein receptors that are involved in platelet adhesion: the GPIb/IX/V and GPIIb/IIIa receptors, respectively.

Platelet aggregation and secretion

Platelets undergo morphological changes upon activation. Platelet shape changes from a disc to a spiny sphere with multiple pseudopodial extensions. The platelet membrane becomes rearranged, with exposure of negatively charged phospholipids that facilitate the interaction with coagulation proteins to form the tenase and prothrombinase complexes. The contents of platelet granules are secreted through the surface-connected canalicular system, with ADP, fibrinogen, and factor V appearing on the platelet surface and in the milieu immediately surrounding the platelet. PDGF is secreted and leads to smooth muscle proliferation. Repeated secretion of PDGF resulting from recurrent episodes of platelet activation increases smooth muscle proliferation and may initiate atherosclerosis. Platelet factor 3 is also expressed after platelet activation. Small pieces of the platelet are able to bud off to form circulating microparticles. Platelet-agonist interactions result in the production or release of a variety of intracellular messenger molecules that facilitate these reactions.

Biochemical processes involved in platelet aggregation and secretion

As platelets are recruited to the area of blood vessel damage, they become activated by a range of agonists including ADP, thrombin, and thromboxanes, which interact with transmembrane receptors. Receptor stimulation results in G protein interactions, which enable activation of enzymes involved in cellular metabolic pathways, in particular, phosphatidylinositol 3-kinase and phospholipase C. Metabolic pathway activation results in the elevation of cytoplasmic calcium and phosphorylation of substrate proteins, which bring about changes in the cytoskeleton, enabling platelet shape change and spreading, release of alpha- and dense-granular contents, stimulation of phospholipase A2 and liberation of TXA2, induction of a procoagulant surface, and activation of GPIIb/IIIa receptors.
A rare, diverse group of disorders of platelet signal transduction have been described, including defects in the agonist receptors for TXA2, ADP and collagen; the membrane G proteins; and the prostaglandin pathway enzymes cyclooxygenase and TXA2 synthetase  Disorders of the platelet storage granules are also well described and includedense granule deficiency, alpha granule deficiency, and combined dense and alphagranule deficiency

 Summary

 The contribution of platelets to hemostasis lies in the formation of the primary hemostatic plug, the secretion of important substances for further recruitment of platelets, the provision of a surface for coagulation to proceed, the release ofpromoters of endothelial repair, and the restoration of normal vessel architecture.
Disruption in any of the above described events and biochemical processes may lead to platelet dysfunction, which may be either inherited or acquired.

 

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Esto es parte del documento:
T R E A T M E N T O F  H E M O P H I L I A APRIL 2008 • NO 19

Published by the World Federation of Hemophilia (WFH), 1999; revised 2008.