Blood vessels must maintain their integrity to effectively deliver blood to the body’s vital organs and tissues. When damage occurs to the walls of a blood vessel, the physiological, reparative mechanism of hemostasis prevents further bleeding. Hemostasis occurs in 2 phases: platelet activation to form a static plug and stabilization of this plug through extrinsic and intrinsic coagulation pathways, known as primary and secondary hemostasis respectively. This article reviews the physiological components of platelet activation during primary hemostasis.
Platelets, otherwise known as thrombocytes, are blood components derived from megakaryocytes originating within the bone marrow. Contained within the cytoplasm of platelets are alpha and dense granules that each release specific mediators necessary for efficient hemostasis, while the exterior of a platelet is coated with receptors targeted by various activating proteins. Naturally, the average lifespan of a platelet is approximately 8 to 10 days. Under normal, healthy circumstances, platelets do not aggregate with one another to form plugs as the endothelial surface of intact blood vessels expresses glycoproteins such as thrombomodulin and releases prostacyclins.
When the endothelium of a blood vessel is damaged, reflexive neural stimulation causes transient vasoconstriction of the involved vessel. Additionally, the damaged cells release endothelin, further promoting vessel constriction in an attempt to limit blood loss. Subendothelial collagen becomes exposed at the site of injury. The plasma glycoprotein von Willebrand factor (vWF), released from the Weibel-Palade bodies of endothelial cells, binds to the exposed collagen and serves as the site of platelet adhesion to the disrupted vessel surface. Platelets bind to vWF using their GPIb receptor. This binding results in a conformational change and activation of the platelet, causing the release of hemostatic mediators from the platelet’s granules, including additional vWF found in alpha granules to potentiate platelet accumulation.
As platelets continue to degranulate and their activation continues along a positive feedback loop, adenosine diphosphate (ADP) released from dense granules bind to P2Y1 and P2Y12 receptors located on the platelet’s membrane, inducing the expression of the GPIIb/IIIa receptor. This newly inserted platelet receptor, along with thromboxane A2 (TXA2) produced by platelet enzyme cyclooxygenase, allows for platelet aggregation. Though its role in hemostasis is currently being studied, serotonin released from dense granules appears to function as another mediator of platelet aggregation while also promoting further vasoconstriction. Fibrinogen from alpha granules acts as a link between GPIIb/IIIa receptors on different platelets. Once platelets have been linked together, a temporary platelet plug has formed, which is later fortified by the coagulation cascade of secondary hemostasis.
Abnormalities of primary hemostasis and platelet activation may arise due to qualitative or quantitative defects of platelets. Clinically these disorders may result in mucosal bleeding or skin bleeding, presenting as petechiae, purpura, or ecchymoses. Abnormal laboratory studies may include prolonged bleeding time or decreased platelet count.
Bernard-Soulier syndrome and Glanzmann thrombasthenia are 2 examples of autosomal recessive qualitative platelet disorders. As described above, platelets are first recruited to a site of damage by vWF and bind to this glycoprotein using GPIb receptors. In Bernard-Soulier syndrome, there is a genetic deficiency of the GPIb receptor, resulting in impaired platelet adhesion to vWF. If a ristocetin-induced platelet aggregation assay were to be performed in a patient with such a deficiency, there would be hypoactive adhesion as ristocetin activates vWF binding to platelet’s GP1b receptor. Glanzmann thrombasthenia is a hereditary disorder that impairs platelet aggregation due to a genetic deficiency of the GPIIb/IIIa receptor. On such a patient’s blood smear, one may expect to see an increase in isolated platelets as platelets are unable to clump together.
The GPIIb/IIIa receptor may also be targeted for destruction in Immune Thrombocytopenic Purpura (ITP). In this condition, IgG autoantibodies are produced by plasma cells in the spleen and target the GPIIb/IIIa receptor on platelets, which the body wrongly recognizes as an antigen. These antibodies then act as signals for the macrophages of the spleen to consume the “tagged” platelets. For this reason, a common finding is a splenomegaly. ITP is the most common cause of thrombocytopenia, a decrease in platelet count, in children and adults and commonly follows a viral illness. Usually, it is self-limited and resolves within weeks, but steroid treatment has been used as initial therapy. Children tend to respond well, but adults tend to relapse. When there is symptomatic bleeding or if there is a concern for intracranial bleeding, intravenous immunoglobulin (IVIG) administration is used to raise the platelet count. However, this is short-lived as the splenic macrophages consume platelets indiscriminately. Therefore, splenectomy is done in refractory cases, as it eliminates the sources of IgG and removes the site of destruction.
Though not a disorder of platelets, von Willebrand disease directly prevents proper platelet adhesion to the subendothelial matrix of injured vessels, thereby increasing the bleeding time as seen in other platelet disorders. The typical subtype of this condition is an autosomal dominant deficiency of vWF and is the most commonly inherited bleeding disorder. As a result of dysfunctional aggregation, patients present with skin and mucosal bleeding, and ristocetin cofactor assay testing is abnormal. Additional laboratory results may show increase partial thromboplastin time (PTT) since vWF also serves as a carrier protein for factor VIII, essential to the extrinsic coagulation pathway. Treatment for von Willebrand disease includes administration of desmopressin, an antidiuretic hormone analog, which increases the release of vWF stored in the Weibel-Palade bodies of vessel endothelium.
In addition to the abovementioned disorders, platelet membrane receptors are also the target of numerous pharmacologic agents. ADP receptor inhibitors, such as clopidogrel or ticagrelor, irreversibly block P2Y12 receptors, preventing the ADP-induced expression of GPIIb/IIIa. Furthermore, drugs such as abciximab and eptifibatide bind to and block GPIIb/IIIa receptors. Thus, both drug classes inhibit platelet aggregation and are used clinically in acute coronary syndrome. Total platelet count must be monitored with the use of these drugs to avoid the risk of bleeding.
Aspirin, a nonsteroidal anti-inflammatory drug commonly used to treat fever and pain, has also been prescribed to lower the risk of myocardial infarction (MI) and stroke in patients with known cardiovascular disease. Aspirin’s role in decreasing mortality after MI and preventing future events is due to its irreversible inhibition of both cyclooxygenase 1 and 2 enzymes, known for producing prostanoids such as TXA2. Thus, aspirin effectively acts as an antithrombotic medication by inhibiting platelet aggregation even at low doses. As expected, bleeding time is increased in patients who consume aspirin, and the drug’s irreversible effect persists until new platelets are produced.
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