Introduction

Platelets are small blood cells with several physiological purposes; the best studied is thrombosis activation. Through their clotting activity and activation of the coagulation cascade, they are crucial to maintaining adequate blood volume in those with vascular injury. The initiation of this activity begins with tissue injury and results in the release and binding of several glycoproteins, growth factors, and clotting factors. The complexity of these processes allows for many pharmacologic targets, which provides several options when it comes to antithrombotic therapy.[1][2][3]

Cellular Level

The outer membrane of platelets is critical for its function in hemostasis. Several receptors that are expressed on its surface either constitutively or after activation allow for adhesion to endothelial surfaces as well as aggregation with other platelets. Inside the platelet, alpha granules and dense granules are present, which contain specific compounds that are critical for a variety of functions. Alpha granules are more numerous and contain compounds like P-selectin, GPIIb/IIIa, GPIb, von Willebrand factor (vWF), factors V, IX, and XIII, and others. Dense granules contain some of these compounds but are principally responsible for storing calcium, potassium, serotonin, and important nucleotides such as ATP and ADP.[4][5][6]

Development

Mature megakaryocytes form platelets. Megakaryocytes are large blood cells whose principal function is the production of platelets. When a megakaryocyte becomes mature, pseudomembrane blebs are extended and eventually break off of the membrane, forming platelets. Platelets, once formed, have an average lifespan of 7 to 10 days, at which point they are removed from the bloodstream.

Function

Platelets maintain hemostasis by adhering to the vascular endothelium, aggregating with other platelets, and initiating the coagulation cascade, leading to the production of a fibrin mesh, which effectively prevents significant blood loss. Platelets are also crucial in inflammation, tissue growth, and immune response. These processes are under the mediation of the release of compounds from the alpha and dense granules, which include numerous growth factors as well as IgG and components of the complement system.[7]

Mechanism

Platelets can become activated in response to exposed collagen, thrombin, ADP, or other compounds. In response to tissue injury, exposed collagen on the subendothelial surface can bind directly to either the platelet or to vWF. The vWF is a molecule that can bind to both collagen and the platelet, via the GPIb receptor on the platelet surface. As a result, vWF acts as a bridge, forming a complex of collagen, vWF, and platelet, which results in adhesion to the vascular surface. Also, exposed collagen can bind directly to the platelet by binding to the GPVI receptor.

Binding to the GPIb and GPVI receptors causes activation of the platelet, beginning intracellular signaling cascades. These cascades result in the release of both alpha and dense granules, as well as activation of other enzymes, such as cyclooxygenase-1 (COX-1), which synthesizes thromboxane A2 (TXA). The release of alpha and dense granules is crucial for the recruitment of nearby platelets and further activation of the platelet.

As a result of degranulation, ADP, TXA, serotonin, fibrinogen, and P-selectin are secreted into the plasma. ADP and TXA are especially important in the activation of platelets. Released ADP binds to P2Y and P2Y receptors on the platelet surface, further increasing signal transduction and activation in the platelet, while TXA binds to thromboxane prostanoid receptors, increasing activation of nearby platelets. Both of these are critical in the recruitment of other platelets to form a large platelet plug. Serotonin acts in a similar, but less potent, way on 5HT receptors.

During activation, GPIIb/IIIa receptors are activated on the platelet’s surface, entering a high-affinity state. GPIIb/IIIa receptors are responsible for binding to fibrinogen. Since two platelets may bind a molecule of fibrinogen, platelets begin cross-linking, forming a larger platelet plug. Additionally, by activating the coagulation cascade with the release of clotting factors earlier during activation, the platelets cause an increased level of thrombin in the blood. Thrombin is a very potent platelet activator of platelets itself but also results in the cleavage of fibrinogen to fibrin. This conversion causes the formation of a stronger link between platelets, converting the soluble fibrinogen into an insoluble fibrin mesh.[8]

Related Testing

The monitoring of platelet quantity and function is frequently useful in evaluating the bleeding risk in hospitalized patients. In healthy patients, platelets are incredibly numerous, with a range of 150 to 350 x10/L. A drop in this number can indicate the consumption of platelets by a condition such as disseminated intravascular coagulation, or autoimmune destruction of platelets, as in immune thrombocytopenia.[9][10]

Clinicians can monitor the function of platelets by evaluating the bleeding time, which evaluates the time between breaking the vasculature and the formation of an effective platelet plug. This time may be elevated in conditions like uremia, in which platelet count is normal but demonstrates impaired function. 

Clinical Significance

Disorders of platelet function or quality are clinically significant conditions with dangerous ramifications. Immune thrombocytopenia represents a condition in which antibodies are formed against the GPIIb/IIIa receptor of the platelets, resulting in the destruction of platelets. As expected, the ability of the body to effectively clot in response to vascular damage becomes significantly reduced. Intrinsic deficiencies, such as GPIb receptor deficiency, as seen in Bernard-Soulier syndrome, acts to decrease the adhesion of platelets to the endothelial surface, leading to a similar result.

The complex cascade involved in platelet activation allows for inhibition at several steps to avoid or decrease the risk of thrombosis. The most well-known of these inhibitors is aspirin, which acts as an irreversible inhibitor of COX, thus inhibiting the formation of TXA. As a result, platelets are unable to aggregate as effectively, thus decreasing the likelihood of clot formation or propagation.

More recently, P2Y receptor blockers and drugs that interfere with the fibrinogen-GPIIb/IIIa binding process have emerged as powerful tools in thrombosis prevention. P2Y receptor blockers, such as clopidogrel, act to decrease the risk of thrombosis by preventing ADP from binding to its receptors on platelet surfaces. These drugs are frequently used in combination with aspirin to reduce thrombosis further. Additionally, Abciximab, a monoclonal antibody to the GPIIb/IIIa receptor, and other GPIIb/IIIa receptor inhibitors (such as tirofiban) also function to decrease thrombosis by inhibiting platelet cross-linking directly.