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Platelet biology and mechanism of anti-platelet drugs

Platelet biology and mechanism of anti-platelet drugs
Literature review current through: Jan 2024.
This topic last updated: Nov 17, 2023.

INTRODUCTION — The platelet is a circulating anucleate disc-shaped cell, responsible for initiation of the hemostatic mechanisms that repair injury to the vascular endothelium. This topic discusses the biology of these platelet functions and the mechanism of action of various drugs that block them.

Separate topics review:

Platelet function testing – (See "Platelet function testing".)

Inherited platelet function disorders – (See "Inherited platelet function disorders (IPFDs)".)

Interaction of platelets with clotting factors – (See "Overview of hemostasis".)

Platelet production – (See "Megakaryocyte biology and platelet production".)

Thrombopoietin – (See "Biology and physiology of thrombopoietin" and "Clinical applications of thrombopoietic growth factors".)

DEFINITIONS AND REFERENCE RANGE — The reference range for platelet count in adults is 150,000 to 450,000/microL. (See "Laboratory test reference ranges in adults", section on 'Platelet count'.)

Other definitions and evaluation for abnormalities of platelet number are presented separately:

Definitions

Thrombocytopenia (mild, moderate, and severe) – (See "Diagnostic approach to thrombocytopenia in adults", section on 'Definitions and areas of concern'.)

Thrombocytosis – (See "Approach to the patient with thrombocytosis", section on 'Terminology'.)

Evaluation

Thrombocytopenia – (See "Approach to the child with unexplained thrombocytopenia" and "Diagnostic approach to thrombocytopenia in adults".)

Thrombocytosis – (See "Approach to the patient with thrombocytosis".)

OVERVIEW OF PLATELET FUNCTION

Role in hemostasis — Platelets are responsible for the first phase of hemostasis, referred to as primary hemostasis [1]. (See "Overview of hemostasis", section on 'Phases of the hemostatic process' and "Overview of hemostasis", section on 'Formation of the platelet plug'.)

There are four major steps in the primary hemostasis process (figure 1):

Adhesion to the site of injury (typically, subendothelial collagen)

Activation and secretion

Aggregation

Interaction with coagulation factors (fibrinogen and tissue factor)

Adhesion to collagen – Circulating platelets do not normally encounter the connective tissue matrix that lies beneath vascular endothelial cells. Once a break within the integrity of this vascular lining occurs, platelets are exposed to, and interact with, collagen fibrils. Platelet interactions with collagen not only provide a surface for platelet adhesion, but also serve as a strong stimulus for platelet activation. This results in signaling pathways that induce platelets to change their shape, spreading along the collagen fibrils and to secrete thromboxane A2 (TxA2) and adenosine diphosphate (ADP) into the circulation. The released thromboxane A2 and ADP stimulate neighboring platelets, causing them to become activated and in turn to secrete additional thromboxane A2 and ADP.

Adhesion to fibrinogen – Activated platelets not only secrete thromboxane A2 and ADP, they also directly bind to the circulating coagulation protein fibrinogen, via the abundant platelet integrin alphaIIbbeta3 (previously called glycoprotein [GP]IIb/IIIa) [2,3]. Fibrinogen (and fibrin) can simultaneously bind two alphaIIbbeta3receptors and function as a link between two platelets (figure 1). This platelet-fibrinogen-platelet connection initiates the process of platelet aggregation [1]. Since each platelet has 40,000 to 80,000 copies of alphaIIbbeta3on its surface, very large clumps (or aggregates) of platelets can assemble at the site of platelet activation [4,5]. A cross-linked fibrin clot ultimately stabilizes the growing platelet aggregate. (See "Disorders of fibrinogen", section on 'Biology'.)

Interaction with tissue factor – In addition to collagen, ADP, and thromboxane A2, other agonists can activate platelets at sites of vascular injury. Tissue factor, which is expressed on all non-vascular cells, is exposed to circulating blood upon disruption of the protective endothelial layer of the vasculature. Tissue factor can interact with factor VIIa to promote local coagulation, and ultimately the generation of thrombin, the most potent of the platelet agonists. Platelets facilitate this process by providing procoagulant phospholipids that accelerate thrombin generation (figure 2). Consequently, platelet activation and fibrin deposition are intimately linked, maximizing the growth and strength of the hemostatic plug. (See "Overview of hemostasis", section on 'Clotting cascade and propagation of the clot'.)

Role in inflammation, cancer, and wound healing

Thromboinflammation – In addition to hemostasis, platelets recruit leukocytes to sites of inflammation, a component of immunity and host defense.

Most evidence suggests that platelets are proinflammatory and initiate a process called thromboinflammation.

Thrombosis associated with COVID-19 is one example of this phenomenon [6]. (See "COVID-19: Hypercoagulability", section on 'Pathogenesis'.)

Platelets may also contribute to the immune response to malaria [7]. (See "An overview of the innate immune system", section on 'Other cells that contribute to innate immunity' and "Pathogenesis of malaria", section on 'Pathophysiology'.)

Other roles – Platelets also contribute to other biologic processes (physiologic and pathologic) including:

Liver regeneration

Dissemination of cancer metastasis

Inflammatory arthritis

Many of these functions for platelets are mediated by the secretion of platelet granules, which contain cytokines and growth factors. (See "Megakaryocyte biology and platelet production", section on 'Granules' and "Inherited platelet function disorders (IPFDs)", section on 'Conceptual framework'.)

Wound healing – Because platelets contain so many growth factors within their granules, some investigators have attempted to accelerate wound healing by injecting platelets suspended within plasma (platelet-rich plasma [PRP]). However, despite widely reported anecdotes and testimonies about the merits of PRP therapy, well-conducted randomized trials of administering PRP have shown this approach to be of no benefit. The evidence is discussed in separate topic reviews:

Osteoarthritis – (See "Management of knee osteoarthritis", section on 'Platelet-rich plasma' and "Investigational approaches to the management of osteoarthritis", section on 'Platelet-rich plasma'.)

Plantar fasciitis – (See "Plantar fasciitis", section on 'Ineffective and experimental treatments'.)

Tendinopathy – (See "Overview of the management of overuse (persistent) tendinopathy", section on 'Autologous blood and platelet-rich plasma injection' and "Elbow tendinopathy (tennis and golf elbow)", section on 'Platelet-rich plasma and other biologic injections' and "Adductor muscle and tendon injury", section on 'Platelet rich plasma (PRP) injections' and "Biologic therapies for tendon and muscle injury", section on 'Studies of PRP use for muscle injury'.)

PLATELET RECEPTORS AND THEIR AGONISTS

General principles of receptor signaling

G-protein coupled receptors – Most platelet agonists stimulate G-protein coupled cell surface receptors that span the platelet membrane; these receptors are discussed below.

Thrombin – PAR1 (See 'Thrombin receptor (PAR1)' below.)

Collagen – Glycoprotein (GP)Ia/IIa and GPVI (See 'Collagen receptors (GPIa/IIa and GPVI)' below.)

ADP – P2Y1 and P2Y12 (See 'ADP receptors (P2Y1 and P2Y12)' below.)

Epinephrine – Adrenergic receptors (See 'Adrenergic (epinephrine) receptors' below.)

Thromboxane A2 (See 'Thromboxane receptor' below.)

The cytoplasmic surface of these receptors interacts with heterotrimeric G-proteins located on the cytoplasmic side of the platelet's plasma membrane, as illustrated in the figure (figure 3). These G proteins consist of an alpha subunit that binds guanosine triphosphate (GTP) or guanosine diphosphate (GDP) and a beta-gamma heterodimeric subunit [8]. When the alpha subunit is bound to GDP, the G-proteins are inactive. Agonist-stimulated receptors promote the replacement of GDP with GTP, switching on the G protein. G protein-coupled receptors typically have a limited duration of activity, after which they are turned off by phosphorylation and in some cases cleared from the cell surface by endocytosis.

Receptor alpha subunit subclass – The subclass of the receptor alpha subunit characterizes the function of different G-protein heterotrimers and in turn determines the role of the receptors that associate with them. G-alpha subclasses and their downstream effects include:

G alpha-subclass "q" – Stimulate phosphoinositide hydrolysis by phospholipase C-beta (PLC-beta) [9].

G alpha-subclass "s" – Stimulate cyclic AMP (cAMP) formation [10].

G alpha-subclass "I" – Inhibit the production of cAMP [10].

G alpha-subclass "i" – Stimulate phosphatidylinositol 3-kinase (PI3K-gamma) and phospholipase C-beta.

G alpha-subclass "12/13" – Stimulate signaling pathways leading to platelet shape-change and phosphoinositide hydrolysis [11].

Strong and weak agonists – Platelet agonists are sometimes classified as strong or weak, presumably reflecting differences in the sets of intracellular signals they evoke.

Strong agonists – Thrombin (generated by the coagulation cascade) and collagen (exposed when the vascular endothelium is wounded) potently stimulate phosphoinositide hydrolysis and are relatively unaffected by cyclooxygenase (COX) inhibition. (See 'Specific drugs (listing)' below.)

Thromboxane A2 (TxA2), generated by platelet cyclooxygenase 1 (COX-1), is a strong agonist. Its production is blocked by COX inhibitors. (See 'Thromboxane receptor' below and 'COX inhibitors (aspirin and other NSAIDs)' below.)

Weaker agonists – ADP (released from platelet dense granules) and epinephrine (released from the adrenal medulla in response to stress) have little or no ability to induce phosphoinositide hydrolysis and are more dependent on an intermediate role of inducing thromboxane A2 production to mediate their effects. (See "Megakaryocyte biology and platelet production", section on 'Granules' and "Surgical anatomy of the adrenal glands", section on 'Adrenal medulla function'.)

Specific receptors and their antagonists

Thrombin receptor (PAR1) — Thrombin (factor IIa) is produced by the coagulation cascade by cleavage of prothrombin (factor II). Thrombin is the enzyme that cleaves fibrinogen to fibrin. Platelets and endothelial cells also contribute to thrombin generation by providing a phospholipid surface to assemble multicomponent complexes responsible for cleaving prothrombin to thrombin. (See "Overview of hemostasis", section on 'Thrombin generation'.)

Thrombin is arguably the most potent activator of platelets. When added at picomolar (10-12 Molar) concentrations to platelets in vitro, thrombin causes phosphoinositide hydrolysis, thromboxane A2 production, activation of signaling cascades, and an increase in cytosolic free calcium concentration. These pathways lead to platelet spreading and filopodial extension, aggregation, and granule secretion [9]. (See 'Platelet activation' below.)

The primary thrombin receptor on platelets is called protease-activated receptor 1 (PAR1). Thrombin receptors are activated by cleavage at a specific site, exposing a new amino-terminus (the "tethered ligand") that interacts with residues in the second extracellular loop of the receptor [12]. This interaction results in activation of the G-proteins on the cytoplasmic surface of the receptor, leading to additional signaling events. (See 'Second messenger signaling' below.)

There are approximately 2000 molecules of intracellular G alpha subunits (subclasses q and 12/13) coupled to extracellular PAR1 on the surface of human platelets [13]. Since platelets synthesize very little protein, they have no real ability to replace cleaved receptors with new uncleaved receptors. As a result, platelets usually respond to thrombin only once.

Vorapaxar is an orally active selective PAR1 antagonist. (See 'PAR1 inhibitor (vorapaxar)' below.)

Because thrombin is such a strong platelet activator, drugs such as COX inhibitors may reduce but do not eliminate platelet responses to thrombin. (See 'COX inhibitors (aspirin and other NSAIDs)' below.)

Collagen receptors (GPIa/IIa and GPVI) — Subendothelial collagen has been long recognized as an important substrate for platelet adhesion and a potent platelet agonist. It is exposed at sites of tissue injury.

The interaction between platelets and collagen is complex. In response to collagen binding, platelet phosphoinositide undergoes hydrolysis, thromboxane A2 is produced, signaling cascades are activated, and cytosolic calcium increases [14].

Platelets possess two collagen receptors [14]; experiments using receptor-blocking antibodies, heterologously expressed receptors, and genetically altered mice have elucidated the relative roles of each of these proteins [15,16]:

GPIa/IIa – Glycoprotein (GP)Ia/IIa, also called alpha2beta1 or VLA-2, is a member of the integrin family of adhesion receptors and primarily serves as an anchor for platelets to attach to collagen exposed after disruptions in the vascular endothelial layer (figure 1) [15].

A patient with an acquired deficiency of this integrin (GPIa/IIa) exhibited a mild bleeding diathesis [17].

GPVI – GPVI is also an important collagen receptor, as evidenced by patients who lack GPVI or who have developed anti-GPVI autoantibodies associated with bleeding disorders [18-20]. GPVI serves as the primary collagen agonist receptor and is responsible for collagen-induced platelet aggregation and secretion. It also can serve as a collagen-adhesion receptor, at least under low shear conditions.

One patient with a mild bleeding disorder due to an autoantibody against GPVI had thrombocytopenia and reduced collagen response [19]. Other patients have a more severe bleeding disorder, often associated with immune dysfunction or autoimmune disease [20].

There are no drugs that specifically block GPIa/IIa or GPVI. Because thrombin is such a strong platelet activator, drugs such as COX inhibitors may reduce but do not eliminate platelet responses to thrombin.

ADP receptors (P2Y1 and P2Y12) — ADP is a weaker platelet agonist than thrombin and collagen.

ADP is stored in platelet dense granules and released upon platelet activation. It interacts with two G-protein-coupled platelet receptors, P2Y1 and P2Y12 [21,22]. In addition to ADP, these receptors can be stimulated by several pyrimidine and purine agonists [23]. Platelets also have receptors for adenosine triphosphate (ATP), but these are ligand-gated ion channels not coupled to G-proteins [24].

In vitro studies and mouse models have demonstrated that simultaneous stimulation of both receptors (P2Y1 and P2Y12) is required for the full platelet ADP response [21].

P2Y1 – P2Y1 is coupled to the platelet G alpha-subclass q subunit. ADP stimulation of P2Y1 causes phosphoinositide hydrolysis, thromboxane A2 production, activation of signaling cascades, and an increase in cytosolic calcium.

P2Y12 – P2Y12 is coupled to the platelet G alpha-subclass "i" subunit. ADP stimulation of P2Y12 inhibits production of cyclic adenosine monophosphate (cyclic AMP).

Heritable bleeding disorders – Congenital deficiency of the P2Y12 is a rare autosomal recessive disorder associated with excessive bleeding [25]. Platelets from affected individuals lack an aggregation response to ADP, even at very high concentrations [26]. These individuals also have a prolonged bleeding time, and impaired aggregation in response to low concentrations of collagen or thrombin. A variety of different pathogenic variants affecting in the P2Y12 receptor have been described [23].

Inhibitory drugs – (See 'P2Y12 inhibitors' below.)

Adrenergic (epinephrine) receptors — Epinephrine is a weaker platelet agonist than thrombin and collagen. It is unique among platelet agonists in that it does not cause aggregation at physiologic doses, but it does activate platelets at high doses. Platelet responses to epinephrine are mediated by G alpha-subclass i (or its highly related G alpha-subclass z)-coupled alpha(2)-adrenergic receptors [27].

It is thought that stress-induced epinephrine in vivo increases the ability of platelets to respond to low doses of other platelet agonists. It acts by blocking formation of cyclic AMP (cAMP). High doses of epinephrine in vitro cause phospholipase C activation. Epinephrine effect can be suppressed by aspirin, suggesting that it is dependent upon thromboxane A2 formation.

Epinephrine mediates numerous other aspects of vascular physiology, as discussed separately. (See "Use of vasopressors and inotropes", section on 'Epinephrine'.)

Thromboxane receptor — Thromboxane A2 (TxA2) is synthesized from arachidonate in platelets by the aspirin-sensitive cyclooxygenase (COX) pathway (figure 4). (See 'Cyclooxygenase (COX)-1' below.)

Once formed, TxA2 can passively diffuse out of the platelet and activate other platelets via the thromboxane receptor, a G alpha-subclass q-coupled receptor (also called TxA2 receptor or prostanoid TP receptor).

Like ADP, TxA2 amplifies the initial signal for platelet activation, thereby helping to stimulate additional platelets. This process is effective locally and is temporally limited by the short half-life of TxA2, which helps to confine the spread of platelet activation to the original area of injury.

There are no thromboxane receptor antagonist drugs, but several drugs that inhibit COX-1 enzymes have anti-platelet activity (platelets express COX-1 but not COX-2). (See 'COX inhibitors (aspirin and other NSAIDs)' below.)

A number of stable endoperoxide/thromboxane analogs have been synthesized, including U46619. When added to platelets in vitro, U46619 causes increased cytosolic calcium, phosphoinositide hydrolysis, protein phosphorylation, aggregation, secretion, and spreading, while having little effect on cAMP formation [28]. Similar responses are seen when platelets are incubated with exogenous arachidonic acid. Since the effects of arachidonate can be inhibited with aspirin, they are thought to be largely due to thromboxane A2 formation.

SECOND MESSENGER SIGNALING — After platelet activation by an agonist, intracellular signaling leads to cytoskeletal reorganization, fibrinogen receptor exposure, and granule secretion. Two central pathways that are activated in response to platelet agonists are phosphoinositide hydrolysis and eicosanoid synthesis.

Phosphoinositide hydrolysis – This pathway begins when phospholipase C cleaves membrane phosphatidylinositol 4,5-bisphosphate (PIP2) to form inositol 1,4,5-trisphosphate (IP3) and diacylglycerol, both of which serve as second messengers (figure 5). (See 'PLC, PKC, and PI3K' below.)

Eicosanoid synthesis – This pathway begins when phospholipase A2 releases arachidonate from membrane phospholipids to form thromboxane A2. (See 'Cyclooxygenase (COX)-1' below.)

Most of the agonists that activate platelets do so via G protein-coupled receptors, and G protein activation is the first step in intracellular signaling leading to platelet second messenger formation. (See 'General principles of receptor signaling' above.)

PLC, PKC, and PI3K

Phospholipase C (PLC) – PLC activation is one of the earliest responses of platelets to most agonists (figure 3). (See 'Platelet receptors and their agonists' above.)

Platelets contain PLC beta and gamma forms.

PLC beta – PLC beta isoforms are activated by G proteins; this is thought to be primarily responsible for the rapid burst of phosphoinositide hydrolysis that occurs during platelet activation by agonists such as thrombin and thromboxane A2 [29,30]. PLC beta1 and PLC beta3 respond best to G alpha, particularly members of the G alpha-subclass q family, while PLC beta2 responds best to G beta-gamma.

Based upon studies with pertussis toxin and genetically modified mice, platelet PAR-1 (thrombin receptor) is thought to be coupled to PLC beta by G alpha isotypes derived from Gq- or G12/13-coupled receptors, and to a lesser extent by G beta-gamma derived from G-subclass i [9,31]. Thromboxane A2 receptors are coupled to PLC beta by G alpha derived from Gq- or G12/13-coupled receptors [9].

PLC gamma – PLC gamma isoforms (predominantly PLC gamma2) are regulated by tyrosine phosphorylation.

Activated PLC hydrolyzes PI-4,5-P(2) into diacylglycerol (DAG) and inositol triphosphate (IP3) (figure 5) [32,33]. DAG is a lipid second messenger that activates protein kinase C (PKC) [34]. IP3 binds to receptors in the dense tubular system and releases sequestered calcium into the cytosol [35,36]. (See 'Calcium' below.)

PKC – Protein kinase C (PKC) isozymes are a family of serine/threonine kinases that play an essential role in transducing signals from activated receptors [37]. Although some discrepancies between different studies on PKC isozyme expression exist, platelets probably express PKC alpha, beta, delta, epsilon, eta, theta, and perhaps zeta and lambda [38].

PKC is activated by DAG and is a key enzyme in the signaling events that follow activation of receptors coupled to phospholipase C (PLC). PKC isozymes also play an important role in megakaryocyte differentiation. (See "Megakaryocyte biology and platelet production", section on 'Origin and differentiation'.)

PKC isozymes phosphorylate multiple cellular proteins on serine and threonine residues that in turn can cause platelet aggregation, release of granular contents, mobilization of intracellular calcium, and changes in cell shape. One of these is pleckstrin, a protein critical for granule secretion [34]. Mice lacking pleckstrin have a complete loss of PKC-mediated granule secretion [34].

PI3K – Phosphatidylinositol 3-kinases (PI3K) are a group of enzymes that phosphorylate the D-3 position of the inositol ring of phosphatidylinositol to produce phosphatidylinositol 3-phosphate (PI3-P), phosphatidylinositol 3,4-bisphosphates (PI3,4-P2), and phosphatidylinositol 3,4,5-triphosphates (PI3,4,5-P2 or PIP3) (figure 5) [39]. Several isoforms of PI3K that phosphorylate PI, PI 4-P, and PIP2 have been described; they are classified according to their catalytic subunit: p110alpha, p110beta, p110gamma, and p110delta.

The role of different PI3K isoforms in platelets and their downstream effectors are under study [40]:

The literature suggests that PI3K is involved in both the initial activation of integrin alphaIIbbeta3 (GPIIb/IIIa) and subsequent stabilization of its interaction with fibrinogen, which leads to irreversible platelet aggregation [41]. (See 'Integrin alphaIIbbeta3 (GPIIb/IIIa) binding to fibrinogen, activation, and platelet aggregation' below.)

Mice lacking the p110gamma catalytic subunit of PI3K have diminished ADP-mediated platelet aggregation [42].

Mice lacking the p110alpha or p110beta subunit of PI3K have reduced signaling in response to platelet collagen receptor (GPVI) activation, whereas platelet activation is normal following stimulation by other platelet agonists such as ADP or thrombin [43].

Calcium — Calcium ions (Ca++) serve as intracellular second messengers; like protein kinases, calcium can affect enzyme activity and protein-protein interactions.

Based on studies with intracellular probes such as Fura-2, the cytosolic free calcium concentration in resting platelets is approximately 0.1 microM. Strong agonists such as thrombin or collagen cause an increase to ≥1.0 microM. Weaker agonists, particularly epinephrine, may have little or no effect.

When platelets are activated, the cytosolic calcium concentration increases because of a combination of calcium release from the dense tubular system and calcium influx across the plasma membrane [44]. The trigger for calcium release from the dense tubular system is 1,4,5-IP3, and the mediators of calcium influx from the extracellular fluid are store-operated calcium channels (SOCC). The source of 1,4,5-IP3 is phospholipase C (PLC)-mediated cleavage of PI(4,5)P2 (figure 5). (See 'PLC, PKC, and PI3K' above.)

The rise in cytosolic calcium contributes to platelet activation by stimulating enzymes that are not optimally active at low calcium concentrations. Examples of these include:

cPLA(2)

PLC

Phosphorylase kinase

Gelsolin

Calpain

Myosin light chain kinase

These in turn mediate additional signaling events as well as cytoskeletal rearrangements important for platelet activation. (See 'Platelet activation' below.)

Cyclooxygenase (COX)-1 — Platelet activation is amplified by passive release of thromboxane A2 (TxA2) from platelet membranes into the extracellular space, followed by its binding to the thromboxane receptor on the surface of other platelets, in a positive feedback loop. (See 'Thromboxane receptor' above.)

TxA2 is synthesized by platelet cyclooxygenase-1 (COX-1). The starting material is arachidonate released from membrane phospholipids by phospholipase A2 during platelet activation [45]. Platelet phospholipase A2 is stimulated by the rise in the cytosolic calcium that accompanies platelet activation. Once released from membrane phospholipids, arachidonate can be metabolized to TxA2 by cyclooxygenase-1 (COX-1) [45].

Once formed, TxA2 can be released by diffusion across the plasma membrane and can activate other platelets through their thromboxane receptors. This leads to platelet phosphoinositide hydrolysis, activation of signaling cascades, increased cytosolic calcium, secretion, aggregation, spreading, and filopodial extension; it has little effect on cAMP formation.

Tyrosine kinases — In addition to serine/threonine kinases such as PKC, platelets contain a large number of tyrosine kinases, some of which become active during platelet activation.

In general, tyrosine phosphorylation can serve two roles:

It can regulate the phosphorylated protein, perhaps by causing a conformational change.

It can provide a binding site for modular domains located in other proteins, such as SH2 domains.

Human platelets contain tyrosine kinases that are receptors for extracellular ligands, as well as large number of nonreceptor (cytoplasmic) tyrosine kinases, including Btk, Tec, Src, Fyn, Lyn, Hck, and Syk. The function of most platelet tyrosine kinases in platelet second messenger signaling remains incompletely understood [46,47]. Studies in knockout mice have identified roles for some of them in signaling pathways downstream of the GPVI collagen receptor, and some of them play critical roles in collagen-induced platelet activation. (See 'Collagen receptors (GPIa/IIa and GPVI)' above.)

Vanadate, an inhibitor of phosphotyrosine phosphatases, promotes platelet activation.

Cyclic AMP and cyclic GMP — Cyclic adenosine monophosphate (cAMP) is generated by adenylate cyclase (also called adenylyl cyclase); cyclic guanosine monophosphate (cGMP) is generated by guanylate cyclase. Guanylate cyclase is activated by nitric oxide (NO), a naturally occurring vasodilator produced by vascular endothelial cells.

Increased intracellular levels of cAMP and cGMP inhibit platelet activation by an unclear mechanism [48]. These cyclic nucleotides are degraded by phosphodiesterases. Phosphodiesterase inhibitors reduce platelet activation by raising the concentrations of platelet cAMP and cGMP. (See 'cAMP phosphodiesterase inhibitors (dipyridamole and cilostazol)' below and 'PDE5 inhibitors (sildenafil, others)' below.)

Platelet agonists – Most platelet agonists suppress cAMP formation by inhibiting adenylate cyclase via one or more of the G-subclass i family members that are expressed in platelets. PGI2 released from activated endothelial cells elevates platelet cAMP levels by stimulating receptors on the platelet surface that are coupled to adenylate cyclase via G proteins. (See 'General principles of receptor signaling' above.)

Anti-platelet drugs – Anti-platelet drugs increase cAMP or cGMP by blocking their degradation. (See 'cAMP phosphodiesterase inhibitors (dipyridamole and cilostazol)' below and 'PDE5 inhibitors (sildenafil, others)' below.)

The mechanism(s) by which cAMP and cGMP block platelet activation remain incompletely understood but are recognized to involve changes in second messenger signaling. (See 'PLC, PKC, and PI3K' above and 'Calcium' above.)

cAMP – Mice lacking the PGI2 receptor have increased thrombosis risk [49]. Increased cAMP impairs phosphoinositide hydrolysis, blunts the increase in cytosolic calcium in response to agonists, and enhances calcium uptake into the dense tubular system.

The effects of cAMP are thought to be mediated by cAMP-dependent protein kinase, also called protein kinase A [50]. Platelet substrates for this enzyme include:

The 24 kDa beta chain of GPIb

Actin-binding protein

Myosin light chain

VASP (vasodilator-stimulated phosphoprotein)

Rap1B

cGMP – Platelets from mice lacking PDE-5A have decreased aggregation, ATP release, P-selectin expression, and integrin aIIbb3 activation [48]. They also have impaired spreading on collagen or fibrinogen and decreased clot retraction. Mechanisms involve [48]:

Reductions in phosphatidylserine exposure, calcium mobilization, and reactive oxygen species (ROS)

Increases in intracellular cGMP

Increased phosphorylation of VASP

Reduced phosphorylation of mitogen activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK)1/2, p38, jun amino-terminal kinase (JNK)

Reduced phosphorylation of AKT (also called protein kinase B [PKB])

PLATELET ACTIVATION

Spreading and filopodial extension — One of the more dramatic events during platelet activation is the metamorphosis that occurs when platelets adhere and spread on exposed collagen fibrils or become activated in the circulation by soluble factors such as thrombin or ADP [51]. In both cases, platelets lose their distinct discoid shape and acquire an irregular morphology with multiple filopodial projections. This transformation is associated with, and largely due to, cytoskeletal rearrangements within the platelet.

Platelet cytoskeletal proteins are arranged in three major structures that support the plasma membrane and determine the morphologies of resting and activated platelets:

Cytoplasmic actin network The cytoplasmic actin network is composed of actin filaments and associated proteins. Actin is a 42 kDa protein that accounts for as much as 20 percent of the total protein content of the platelet [52]. In resting platelets, 40 to 50 percent of the actin is present as filamentous (F)-actin; the remainder is monomeric globular (G)-actin.

During platelet activation, there is a burst of actin polymerization that results in 70 to 80 percent F-actin; this occurs through a coordinated sequence of events in which the actin filaments present in resting platelets are severed and the resultant smaller fragments used to nucleate new, longer actin filaments. This process of actin polymerization is thought to be regulated in part by the increase in levels of a phosphatidylinositol (PI-4,5-P2) that accompanies platelet activation [53]. (See 'PLC, PKC, and PI3K' above.)

Platelet activation is also accompanied by phosphorylation of non-muscle myosin by myosin light chain kinase. Association of myosin with F-actin produces filaments that are anchored to the platelet plasma membrane by attachment, via actin-binding protein, to the GPIb/V/IX complex, which serves as a receptor for von Willebrand factor (VWF). (See 'Platelet binding to collagen (via GPIa/IIa) and VWF (via GPIb/V/IX)' below.)

Genetic variants affecting non-muscle myosin and GPIb/V/IX-VWF interactions are well-described causes of platelet dysfunction. (See "Inherited platelet function disorders (IPFDs)", section on 'MYH9-related disease' and "Inherited platelet function disorders (IPFDs)", section on 'Bernard-Soulier syndrome' and "Inherited platelet function disorders (IPFDs)", section on 'Platelet-type VWD'.)

Membrane-associated cytoskeleton – A rim of membrane-associated cytoskeleton supports the plasma membrane. It is composed of actin, filamin, P235 (talin), vinculin, spectrin, alpha-actinin and several membrane glycoproteins. Filamin is an elongated 280 kDa protein in platelets that binds actin. In resting platelets, filamin is part of a semi-rigid array that helps to maintain the platelet's discoid shape and limits the lateral movement of GPIb. This role is analogous to that performed by spectrin in erythrocytes.

When platelets are activated, newly formed actin filaments bind to actin-binding proteins. Later, the rising cytosolic calcium concentration activates calpain, an enzyme that cleaves actin-binding protein, severing the link to GPIb.

Microtubule-based marginal band – The marginal band consists of a single, tightly wound microtubule coil that encircles the platelet perimeter and helps to maintain its discoid shape [54]. During platelet activation, the microtubule coil contracts. Initially it was thought contraction of the marginal band was required for stable adhesion of platelets under arterial shear pressures. However, newer evidence has challenged the nature of this marginal band and its function during both resting and activated platelet states [54-56].

Platelet binding to collagen (via GPIa/IIa) and VWF (via GPIb/V/IX) — Platelet filopodia are extremely adhesive to the subendothelial matrix. (See 'Spreading and filopodial extension' above.)

Two of the main proteins they adhere to are collagen and von Willebrand factor (VWF).

Collagen – Collagen on the subendothelial surface interacts with platelet receptor GPIa/IIa.

VWF – VWF adheres to subendothelial collagen that is exposed to the bloodstream when the vascular endothelium is disrupted. The ability of VWF to bind to subendothelial collagen is augmented in areas of high sheer stress (high vascular flow). Collagen-bound VWF can simultaneously bind to the platelet receptor GPIb/V/IX. Therefore, VWF acts as a bridge that allows platelets to indirectly associate with subendothelial collagen. (See "Pathophysiology of von Willebrand disease", section on 'Bridging between platelets and vascular subendothelium'.)

The heritable platelet function disorder caused by deficiency of GPIb (and deficient platelet binding to VWF) is Bernard Soulier syndrome (BSS). (See "Inherited platelet function disorders (IPFDs)", section on 'Bernard-Soulier syndrome'.)

Abnormal GPIb/V/IX that accelerates clearance of VWF causes platelet-type von Willebrand disease (VWD). (See "Inherited platelet function disorders (IPFDs)", section on 'Platelet-type VWD'.)

Caplacizumab binds to VWF and blocks its ability to interact with platelet GPIb/V/IX; it is used for immune-mediated thrombotic thrombocytopenic purpura (TTP). (See "Immune TTP: Initial treatment", section on 'Anti-VWF (caplacizumab)'.)

Drugs that target platelet GPIb/V/IX are under investigation [57].

Integrin alphaIIbbeta3 (GPIIb/IIIa) binding to fibrinogen, activation, and platelet aggregation — Integrin alpha2beta3 (previously called GPIIb/IIIa) is a platelet surface receptor for fibrinogen, the protein that gets converted to fibrin at the end of the coagulation cascade. (See "Disorders of fibrinogen", section on 'Functions in hemostasis and other processes'.)

Circulating platelets do not normally bind fibrinogen or stick to each other unless they have been activated. The process of transforming alphaIIbbeta3 (GPIIb/IIIa) on the platelet surface into a competent high-affinity receptor for fibrinogen was one of the most elusive aspects of platelet signaling. It results in a conformational change that is the final common pathway in platelet responses to most agonists, making it a frequent target for drug development. The process whereby intracellular events alter the conformation of integrin alphaIIbbeta3 on the cell surface is referred to as "inside-out" signaling (figure 1) [2,58,59]. (See "Inherited platelet function disorders (IPFDs)", section on 'Conceptual framework'.)

The conformational change in integrin alphaIIbbeta3 requires binding of talin and kindlin-3 to the cytoplasmic tail of integrin beta3 [3]. The binding of these two proteins to the cytoplasmic side of the receptor opens the extracellular side and thereby allows it to bind fibrinogen. Fibrinogen binding and platelet aggregation induce and propagate a series of intracellular signaling events, including tyrosine and serine/threonine kinase and phosphatase activation, referred to as "outside-in" signaling. Normally, this should occur only at sites of vascular injury.

Counteracting this platelet activation pathway are a number of internal and external controls that dampen the intracellular signals that would otherwise allow inappropriate platelet activation and thrombosis. These controls include:

Tight regulation of the cytosolic calcium concentration

Intracellular phosphatases that limit signaling through kinase-dependent pathways

Extracellular ADPases that hydrolyze released ADP

Inhibitory effects of PGI2 and nitric oxide (NO) released from endothelial cells

Collectively, these provide a threshold that helps to prevent platelet activation at inappropriate times and places.

The heritable platelet function disorder caused by deficiency of integrin alphaIIbbeta3 is Glanzmann thrombasthenia. (See "Inherited platelet function disorders (IPFDs)", section on 'Glanzmann thrombasthenia'.)

Anti-platelet drugs that block integrin alphaIIbbeta3 (also called GPIIb/IIIa inhibitors) are potent blockers of platelet aggregation. (See 'GPIIb/IIIa inhibitors' below.)

Secretion (granule exocytosis) — Once a platelet is activated, platelet granules release a variety of substances that stimulate or inhibit platelets or other blood and vascular cells. The granules are generated during platelet formation; some are taken up by the developing platelet. (See "Megakaryocyte biology and platelet production", section on 'Granules'.)

Platelets contain three types of granules:

Dense granules – Contain platelet agonists (ADP, ATP, serotonin) that serve to amplify platelet activation.

Alpha granules – Contain proteins that enhance platelet adhesion to sites of injury and developing thrombi (fibrinogen, fibronectin, vitronectin, von Willebrand factor).

Lysosomal granules – Contain glycosidases and proteases with an unclear function in platelet biology [60].

Dense and alpha granule contents can covalently modify the thrombus to affect its mechanical properties, as well as regulate coagulation, contribute to cell adhesive events, and modulate the growth of cells of the vessel wall. Understanding of the mechanisms of platelet secretion has been helped by studies of the SNARE complex (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) in neuronal cell exocytosis. The SNARE machinery regulates the association and subsequent fusion of vesicles with membranes. This process involves a small GTP-binding protein called Arf6 [61]. Platelets contain the three basic components of the SNARE machinery [60]:

t-SNAREs (target receptors)

v-SNAREs (vesicle-associated membrane receptors)

Soluble components (including NSF [N-ethylmaleimide sensitive factor] and NSF-attachment proteins)

Gray platelet syndrome is an alpha granule disorder caused by pathogenic variants in NBEAL2, which encodes a scaffolding protein that shuttles proteins from the endoplasmic reticulum to the alpha granules [62,63]. Gray platelet syndrome and other heritable disorders of platelet granules are discussed separately. (See "Inherited platelet function disorders (IPFDs)", section on 'Gray platelet syndrome'.)

There are no granule-specific anti-platelet drugs; however, all drugs that affect weak agonists such as ADP will affect secretion. Consequently, aspirin and all P2Y12 antagonists may impair platelet secretion [64]. (See 'COX inhibitors (aspirin and other NSAIDs)' below.)

ANTI-PLATELET DRUGS

Clinical uses — A number of drugs are used specifically for their ability to interfere with platelet function, especially in cardiology and vascular medicine. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Rationale'.)

The table summarizes the biologic targets of anti-platelet drugs and the specific drugs that affect these targets.

Use of these agents is discussed in the following separate reviews:

Cardiovascular disease primary prevention – (See "Aspirin in the primary prevention of cardiovascular disease and cancer".)

Cardiovascular disease secondary prevention – (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

Acute coronary syndrome (non-ST elevation) – (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy".)

Acute coronary syndrome (ST elevation) – (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy".)

Coronary stenting – (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients".)

Stroke prevention – (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".)

Specific drugs (listing) — The table summarizes specific drugs and their targets, which are discussed in the following sections.

The functions of selected drug targets are discussed above.

Thrombin receptor – (See 'Thrombin receptor (PAR1)' above.)

ADP receptors – (See 'ADP receptors (P2Y1 and P2Y12)' above.)

Prostaglandin synthesis – (See 'Cyclooxygenase (COX)-1' above.)

Cyclic AMP – (See 'Cyclic AMP and cyclic GMP' above.)

Integrin alphaIIbbeta3 (previously called GPIIb/IIIa) receptor – (See 'Integrin alphaIIbbeta3 (GPIIb/IIIa) binding to fibrinogen, activation, and platelet aggregation' above.)

COX inhibitors (aspirin and other NSAIDs) — Platelets express COX-1, which contributes to the synthesis of thromboxane A2. (See 'Cyclooxygenase (COX)-1' above.)

Aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs; non-selective COX inhibitors) are the most commonly used anti-platelet drugs (table 1).

Aspirin

Mechanism of actionAspirin acetylates COX-1, causing it to be irreversibly inactivated (figure 6). Platelet prostaglandin synthesis is nearly completely inhibited by a single 325 mg oral dose of aspirin or by as little as 30 mg taken daily for 7 to 10 days. In individuals with normally functioning platelets, the effect of aspirin on the bleeding is generally mild. (See 'Cyclooxygenase (COX)-1' above.)

Pharmacokinetics/pharmacodynamics – Since platelets cannot synthesize significant amounts of new protein, inactivation of COX-1 by aspirin blocks TxA2 synthesis for the life of the platelet (approximately seven days). This in turn impairs responses to ADP, epinephrine, arachidonic acid, and low levels of collagen and thrombin; however, platelet responses to higher levels of collagen and thrombin remain intact. (See 'Specific receptors and their antagonists' above.)

The irreversible inactivation of COX-1 by aspirin means that it has a long pharmacodynamic effect and inhibits an individual platelet for the remainder of that platelet's lifespan (up to a week). However, aspirin has a very short pharmacokinetic half-life, so the drug only lasts in the circulation for minutes.

Platelet transfusions – Since aspirin is only present in the bloodstream of someone who has just ingested it, transfused platelets work normally in patients who are taking chronic aspirin therapy. Consequently, platelet transfusions may be appropriate to treat aspirin-associated clinically serious bleeding or certain emergency invasive procedures. This differs from the pharmacodynamic and pharmacokinetic profiles of P2Y12 inhibitors, which have a reversible effect on platelet function but persist in the circulation for weeks. (See 'P2Y12 inhibitors' below and "Platelet transfusion: Indications, ordering, and associated risks", section on 'Antiplatelet agents'.)

Aspirin resistance – "Aspirin resistance" is a term that sometimes refers to patients who have a cardiovascular event despite aspirin therapy. This can occur because of platelet activation that occurs independent of COX-1. "Aspirin resistance" sometimes alternatively refers to the situation where aspirin does not lead to COX-1 inhibition. Causes of this form of aspirin resistance include non-adherence and decreased absorption due to enteric coating. These scenarios and an approach to the evaluation and interventions are presented separately. (See "Nonresponse and resistance to aspirin".)

Other NSAIDs – In contrast to aspirin, other NSAIDs inhibit COX enzymes reversibly [65]. (See "NSAIDs (including aspirin): Pharmacology and mechanism of action".)

The effects of NSAIDs on platelet function are usually not clinically significant. In fact, it has been shown that ibuprofen can be administered safely to patients with hemophilia A [66,67]. However, these drugs are routinely stopped prior to invasive procedures. (See "Nonselective NSAIDs: Overview of adverse effects".)

COX-2 selective NSAIDs have no effect on platelet function because platelets do not express COX-2. This likely contributes to the increased cardiovascular risks associated with COX-2 inhibitors. (See "Overview of COX-2 selective NSAIDs", section on 'Lack of platelet inhibition and use during anticoagulation'.)

GPIIb/IIIa inhibitors — GPIIb/IIIa inhibitors block the final common pathway of platelet aggregation, the cross bridging of platelets mediated by fibrinogen bound to the activated integrin alphaIIbbeta3 receptor (GPIIb/IIIa receptor) on different platelets (figure 1). (See 'Integrin alphaIIbbeta3 (GPIIb/IIIa) binding to fibrinogen, activation, and platelet aggregation' above.)

Anti-platelet drugs that block this activated receptor include monoclonal antibodies (abciximab) and small molecule receptor antagonists (tirofiban, eptifibatide). These agents may also prevent initial adhesion of platelets to the vessel wall. Their use in coronary heart disease is discussed separately. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'Glycoprotein IIb/IIIa inhibitors'.)

P2Y12 inhibitors — P2Y12 inhibitors block the ADP receptor P2Y12 on the platelet surface. (See 'ADP receptors (P2Y1 and P2Y12)' above.)

Drugs that inhibit the P2Y12 receptor include several thienopyridines and non-thienopyridine agents [68]:

Clopidogrel – Oral thienopyridine, irreversible effect

Ticlopidine – Oral thienopyridine, irreversible effect, not available in the United States

Prasugrel – Oral thienopyridine, irreversible effect

Ticagrelor – Oral non-thienopyridine, reversible effect

Cangrelor – Intravenous non-thienopyridine (ATP analog), reversible effect

Clinical use – Use of P2Y12 inhibitors in acute ST-elevation myocardial infarction and cardiovascular risk reduction is discussed separately. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy" and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'P2Y12 use'.)

The timing of drug discontinuation for neuraxial anesthesia is also discussed separately. (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication", section on 'Platelet P2Y12 receptor blockers'.)

Pharmacokinetics/pharmacodynamicsClopidogrel, ticlopidine, and prasugrel are irreversible platelet function inhibitors. They are thienopyridine prodrugs that require metabolism by cytochrome P450 enzymes to the active drug. Platelet inhibition occurs within 24 to 48 hours of the first dose, becomes maximal after four to six days, and may last for 4 to 10 days after drug discontinuation, due to their extended pharmacokinetic and pharmacodynamic half-life. Prasugrel activation is not adversely affected by the common CYP polymorphisms that can reduce the effectiveness of clopidogrel [69-71].

Ticagrelor and cangrelor are not thienopyridines (ticagrelor is a modified pyrimidine; cangrelor is an ATP analog). They do not require metabolic conversion to an active form, so they have the advantage of a more rapid onset of action [22]. They are reversible inhibitors, so they are associated with a more rapid return of platelet function after discontinuation.

Bleeding – These drugs all inhibit platelet ADP receptors and increase the risk of major bleeding to a roughly similar extent; although ticagrelor binds directly to the P2Y12 receptor and can more completely inhibit the sustained platelet aggregation response to ADP than clopidogrel. As a rule, these drugs all increase the risk of bleeding a bit more than aspirin.

When combined with aspirin they appear to have an additive effect. In addition to inhibiting the platelet aggregation response to ADP, these drugs also inhibit platelet responses to low concentrations of other agonists; this is thought to occur because ADP released from dense granules plays a role in those responses. In patients treated with these drugs, platelet aggregation in response to high concentrations of thrombin or collagen is normal.

Platelet transfusions – In contrast to aspirin effect, which can be overcome if needed by platelet transfusion (aspirin irreversibly blocks platelet function but has a very short half-life in the circulation), transfused platelets in a patient taking a P2Y12 inhibitor will become impaired just like the patient's own platelets due to the long half-lives of these drugs. Although patients with serious bleeding on these agents may benefit from platelet transfusions, the benefit may be short-lived and transfusions may need to be repeated if clinically indicated. (See 'COX inhibitors (aspirin and other NSAIDs)' above and "Platelet transfusion: Indications, ordering, and associated risks", section on 'Antiplatelet agents'.)

Clopidogrel resistance – In some individuals with cardiovascular disease, platelets appear to have "resistance" to clopidogrel, with increased risk for recurrent vascular events [72]. Possible causes are discussed separately. These include variants in the P2RY12 gene, which encodes P2Y12, or, more commonly, altered metabolism of clopidogrel due to changes in the cytochrome P450 system and/or concurrent medications including warfarin or proton pump inhibitors. The clinical significance of these in vitro phenomena is unclear. (See "Clopidogrel resistance and clopidogrel treatment failure".)

cAMP phosphodiesterase inhibitors (dipyridamole and cilostazol) — Intracellular cyclic adenosine monophosphate (cAMP) blocks platelet activation, and thrombin decreases platelet cAMP [73].

Dipyridamole and cilostazol block cAMP metabolism by cAMP phosphodiesterase (also called phosphodiesterase 3A [PDE-3A]), in turn increasing cAMP levels and inhibiting platelet function [73]. These drugs also act as vasodilators via their effects on cAMP in smooth muscle.

Dipyridamole – Blocks cAMP phosphodiesterase in platelets [50]. Its efficacy as an antiplatelet agent has been debated. (See "Overview of stress radionuclide myocardial perfusion imaging", section on 'Dipyridamole' and "Overview of hemodialysis arteriovenous graft maintenance and thrombosis prevention", section on 'Dipyridamole and aspirin'.)

Cilostazol – Blocks cAMP phosphodiesterase in platelets and vascular smooth-muscle cells. It is a potent anti-platelet agent and vasodilator. (See "Antithrombotic therapy for elective percutaneous coronary intervention: Clinical studies", section on 'Cilostazol' and "Management of claudication due to peripheral artery disease", section on 'Cilostazol'.)

PDE5 inhibitors (sildenafil, others) — Intracellular cyclic guanosine monophosphate (cGMP) blocks platelet activation, and phosphodiesterase 5 (PDE-5) metabolizes cGMP.

PDE-5 inhibitors (sildenafil, tadalafil, avanafil, and vardenafil) inhibit platelet function by keeping cGMP levels high. These drugs also act as vasodilators via similar effects on smooth muscle. They potentiate the effect of nitric oxide (NO).

These agents were originally developed as vasodilators but have since been established primarily as treatments for erectile dysfunction. (See "Treatment of male sexual dysfunction", section on 'Initial therapy: PDE5 inhibitors'.)

They are also used to treat

Pulmonary hypertension. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'WHO functional class II and III or low/intermediate risk (combination oral therapy)'.)

Priapism in sickle cell disease. (See "Priapism and erectile dysfunction in sickle cell disease", section on 'PDE-5 inhibitors (sildenafil and tadalafil)'.)

Contraindications such as concomitant nitrates and certain other vasodilators are discussed separately. (See "Sexual activity in patients with cardiovascular disease".)

PAR1 inhibitor (vorapaxar) — Vorapaxar is an orally active selective inhibitor of the thrombin receptor. It blocks thrombin-mediated platelet activation without interfering with thrombin-mediated cleavage of fibrinogen [74]. (See 'Thrombin receptor (PAR1)' above.)

Its binding to PAR1 is reversible, but its half-life of receptor binding and half-life of elimination are very long; as a result, its effect on platelet inhibition lasts for up to four weeks after discontinuation.

Approved indications include secondary prevention of coronary artery disease and peripheral vascular disease. Despite approval for these indications, its benefit beyond standard anti-platelet therapy remains unclear. Its main use is in peripheral artery disease. (See "Overview of lower extremity peripheral artery disease", section on 'Antithrombotic therapy'.)

Other drugs/mechanisms of action — Certain classes of drugs, including some of those listed above as well as nitrates, heparins, and thrombolytic agents, may also impair platelet function directly or indirectly via one or more mechanisms including:

Toxicity to the bone marrow and/or developing megakaryocytes. (See "Megakaryocyte biology and platelet production".)

Stimulation of anti-platelet antibodies (demonstrated for abciximab, clopidogrel, and heparin). (See "Drug-induced immune thrombocytopenia", section on 'Mechanisms of DITP'.)

GENETIC VARIANTS AFFECTING PLATELET FUNCTION — Some genetic variants that helped determine the function of platelet receptors, signaling, or activation are noted above. A comprehensive discussion of genetic variants that affect platelet function is presented separately. (See "Inherited platelet function disorders (IPFDs)", section on 'Mechanisms and gene variants' and "Inherited platelet function disorders (IPFDs)", section on 'Specific disorders'.)

SUMMARY

Reference range – The reference range for platelet count in adults is 150,000 to 450,000/microL. Links to discussions of the causes and evaluation of thrombocytopenia and thrombocytosis are listed above. (See "Laboratory test reference ranges in adults", section on 'Platelet count' and 'Definitions and reference range' above.)

Functions – Platelets are responsible for the first phase of hemostasis (primary hemostasis), which is illustrated in the figure (figure 1), in which they:

Adhere to the site of injury (typically, subendothelial collagen)

Become activated and secrete substances that promote clotting

Aggregate together with other platelets

Interact with coagulation factors (fibrinogen and tissue factor)

Secondary hemostasis (the clotting factor cascade) generates thrombin, which cleaves fibrinogen to fibrin; crosslinking of fibrin creates a stable clot. Platelets also have roles in inflammation, cancer, and wound healing. (See 'Overview of platelet function' above and "Overview of hemostasis".)

Platelet agonists – Most platelet agonists stimulate G-protein coupled cell surface receptors that span the platelet membrane and interact with heterotrimeric G-proteins located on the cytoplasmic surface of the plasma membrane (figure 3). Thrombin and collagen are strong agonists that potently stimulate phosphoinositide hydrolysis. ADP and epinephrine are weaker agonists that depend on thromboxane A2 production to mediate their effects. (See 'Platelet receptors and their agonists' above.)

Signaling – Activation by agonists stimulates intracellular signaling pathways. Central pathways include:

Phosphoinositide hydrolysis via phospholipase C (PLC), protein kinase C (PKC), and phosphatidylinositol 3-kinases (PI3K). (See 'PLC, PKC, and PI3K' above.)

Eicosanoid synthesis, mediated by cyclooxygenase-1. (See 'Cyclooxygenase (COX)-1' above.)

These pathways rely on increases in intracellular calcium ions and tyrosine phosphorylation, and they are balanced by cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which inhibit platelet activation. (See 'Calcium' above and 'Tyrosine kinases' above and 'Cyclic AMP and cyclic GMP' above.)

Activation – When platelets adhere and spread on exposed collagen fibrils or become activated in the circulation they lose their discoid shape and acquire an irregular morphology with multiple filopodial projections. This is largely due to cytoskeletal rearrangements involving cytosolic actin, the membrane cytoskeleton, and the microtubule-based marginal band. Intracellular events alter the conformation of integrin alphaIIbbeta3 (previously called GPIIb/IIIa) on the platelet surface, allowing the platelet to bind fibrinogen, which induces further activation and secretion of granule contents that include additional platelet agonists. (See 'Platelet activation' above.)

Anti-platelet drugs – Available anti-platelet drugs target many of the processes described above. The most commonly used are aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs), which inhibit platelet cyclooxygenase-1 (COX-1; platelets do not contain COX-2). GPIIb/IIIa inhibitors and P2Y12 inhibitors are primarily used for cardiovascular indications. Phosphodiesterase inhibitors affect platelet function but are primarily used for their effects on the vasculature for indications including erectile dysfunction and pulmonary hypertension. Other drugs that target specific receptors or signaling pathways are also available. (See 'Specific drugs (listing)' above.)

Related discussions – Separate topic reviews discuss:

Platelet production – (See "Megakaryocyte biology and platelet production".)

Platelet roles in hemostasis – (See "Overview of hemostasis", section on 'Formation of the platelet plug'.)

Genetic variants affecting platelet function – (See "Inherited platelet function disorders (IPFDs)".)

Platelet function testing – (See "Platelet function testing".)

Indications for anti-platelet drugs – (See 'Clinical uses' above.)

Platelet transfusion – (See "Platelet transfusion: Indications, ordering, and associated risks".)

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Topic 6683 Version 34.0

References

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