Platelet Plugging
| Overview |
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- Platelets are normally smooth, free-floating, disc-shaped blood elements, roughly one-half to one-third the size of erythrocytes. However, upon encountering torn vessels, platelets rapidly stick to the site of injury and aggregate into a "Platelet Plug" that can stop blood loss from small tears in the vasculature. Our bodies develop thousands of such small tears daily and when platelet levels fall below a particular threshold, numerous tiny hemorrhages can form on the skin, known as petechiae. Platelet plugs are inadequate for larger vascular injuries which require assistance of the coagulation cascade; thankfully, mechanisms exist that connect platelet activation to coagulation.
| Mechanisms |
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- Initiation
- Likely the most powerful initiator of platelet activation following trauma is disruption of a vessel's intact endothelium and exposure of the underlying Extracellular Matrix (ECM). Firstly, an intact endothelium provides a poor surface for platelet adherence. Secondly, a healthy endothelium secretes a number of soluble factors that actively dampen platelet activation. Disruption of the endothelium also exposes the highly thromobogenic sub-endothelial extracellular matrix that upon coming into contact with platelets causes their direct activation as described below.
- Activation, Propagation, and Aggregation
- Platelets possess surface receptors that can directly bind to the ECM; however, this interaction is highly facilitated by von Willibrand Factor (vWF) which bridges the connection. Binding to the ECM not only adheres the platelet to the site of injury but also triggers a number of mechanisms which promote platelet aggregation. These mechanisms, collectively known as "platelet activation" include the synthesis of Thromboxane A2, release of ADP stored within internal granules, as well as changes to surface GPIIb/IIIa receptors. Together these mechanisms serve to locally generate large numbers of platelets that are highly adherent to the exposed vessel wall and to one another, leading to the rapid development of an enlarging platelet plug at the site of injury. Importantly, these mechanisms of platelet activation are targeted by a variety of drugs that act as platelet inhibitors.
- Thromboxane A2: Thromboxane A2 is rapidly synthesized from arachidonic acid by the enzyme COX-1 once platelets are activated. Thromboxane A2 rapidly diffuses to nearby platelets and triggers their activation.
- ADP: ADP is rapidly released from platelet granules, diffusing to nearby platelets and triggering their activation.
- GPIIb/IIIa: GPIIb/IIIa are receptors present on the surface of platelets. Upon platelet activation, GPIIb/IIIa receptors undergo a conformational change that allows them to bind plasma fibrinogen. Because multiple GPIIb/IIIa receptors from different platelets can bind the same fibrinogen molecule, this allows for rapid aggregation of activated platelets.
- Connection to Coagulation
- Release of granules by platelets is also accompanied by expression of the "Phospholipid Complex" on the platelet surface which triggers the Intrinsic arm of the coagulation cascade. This phospholipid complex also accelerates many of the reactions of the coagulation cascade by providing a physical substrate upon which these reactions can proceed. Because the complex is localized to the platelet surface, this helps maintain coagulation within a geographically delimited area and prevents rapid extension into healthy vasculature. Finally, the secretory granules described above possess a number of soluble factors, especially calcium, that facilitate activation of the coagulation cascade.
- While a platelet plug on its own is relatively unstable, the inclusion of fibrin (courtesy of the coagulation cascade), renders the end result highly stable and capable of long-term hemostasis at sites of injury