Platelet Aggregation - Causes and Clinical Conditions

Introduction

Platelets are small, disc-shaped cells present in the circulating blood. They are also called megakaryocytes or thrombocytes. They are produced from the bone marrow. Platelets play a vital role in preventing blood loss and maintaining hemostasis (regulating blood volume). They are activated during injury to blood vessels (vasculature) and accumulate at the site of vascular injury to arrest the bleeding.

Platelet aggregation is one of the most crucial steps in the proper functioning of platelets. It is a finely regulated complex process where the reduced accumulation of platelets leads to uncontrolled bleeding and increased aggregation of platelets leads to clot formation in normal blood vessels resulting in several complications. Thrombotic disorders like cardiovascular diseases and stroke occur due to excessive platelet aggregation. Assessment of platelet aggregation through various laboratory methods helps in the prevention of life-threatening consequences that occur due to its altered dysfunction.

How Does Platelet Aggregation Occur?

Platelet aggregation is a step-wise process mediated by several clotting factors and chemical mediators of clot formation. It occurs during the initial stages of primary hemostasis leading to the formation of the platelet plug. This platelet plug transiently covers the injured site and conceals the exposed inner surface of blood vessels. The following events are associated with platelet aggregation.

• Platelet activation occurs when the platelets remain in their inactive form during normal blood flow in intact blood vessels.

• Any injury to the blood vessels or discontinuation of the endothelium (innermost layer of the blood vessel) leads to the activation of thrombin (an enzyme that promotes the clotting mechanism).

• The release of thrombin triggers the overall blood clotting hemostasis and activates platelets.

• Platelet adhesion occurs when the activated platelets come in contact with subendothelial (inner layer of the blood vessel) factors like von Willebrand factor (vWF) and fibrinogen that are exposed due to injury in the inner vascular wall.

• These factors help in anchoring the activated platelets to the affected vessel wall resulting in platelet adhesion.

• Platelet aggregation occurs after the activated platelets stick at the site of injury in a vascular wall, they interact with each other to initiate the formation of platelet aggregates.

• Platelet aggregation is primarily mediated by aggregation factors such as β3 integrin (αIIbβ3), von Willebrand factor, and fibrinogen.

• Platelet aggregation is positively regulated by chemical mediators, where aggregation of platelets accumulates more platelets leading to the formation of a clot or thrombus.

What Are the Biological Factors That Enhance Platelet Aggregation?

• Thrombin enhances platelet aggregation by increasing the binding between adhered platelets and fibrin, where fibrin acts as a net to stabilize the interconnected platelets.

• Calcium and mediators like thromboxane A2 (TXA2) are potent activators of platelet aggregation.

• Shear forces (pressure exerted by blood flow on the vessel walls) in partially obliterated blood vessels are higher which enhances platelet aggregation.

• Inflammation of endothelium due to infections or inflammatory disorders also facilitates the aggregation of platelets.

What Are the Clinical Conditions That Accelerate Platelet Aggregation?

Platelet aggregation is essential for preventing bleeding during vascular injuries. However, platelet aggregation occurring in unfavorable sites like inside an intact vascular vessel leads to obstruction in blood flow and thrombosis. Some of the clinical conditions that activate platelet aggregation are as follows -

• All forms of external vascular injuries (from minor cuts to massive trauma).

• Arteriosclerosis (thickening of arterial walls).

• Atheromatous plaque formation (buildup of fatty material inside the arteries).

• Inflamed endothelium (occurs in skin grafts).

• Bone fractures.

• Emboli (displaced clot).

• Placement of indwelling catheters (central venous catheters).

• Blood clot-promoting agents like tranexamic acid and aminocaproic acid.

• Medications such as hormone therapy and contraceptive pills.

• Risk factors such as smoking and obesity.

• Inherited thrombotic disorders (factor V Leiden).

• Hyperhomocysteinemia.

What Are the Causes That Inhibit Platelet Aggregation?

When platelet aggregation is interfered with or reduced, it results in excessive uncontrolled bleeding during injuries and also spontaneous recurrent bleeding. Clinical conditions that inhibit platelet aggregation are as follows -

• Congenital deficiencies of platelet aggregation factors like von Willebrand factor (vWf) and integrin (αIIbβ3).

• Abnormalities in immune mechanisms such as immune thrombocytopenia (platelet destruction).

• Liver cirrhosis.

• Bone marrow disorders such as multiple myeloma.

• Kidney disease.

• Systemic lupus erythematosus (disseminated intravascular clotting).

• Anti-platelet agents (thienopyridines, glycoprotein inhibitors).

• Drugs such as Aspirin.

• Hemophilia.

• Preeclampsia (high blood pressure during pregnancy).

• Uremia (high levels of urea in the blood).

• Inherited platelet disorders such as Bernier-Soulier syndrome.

• After major cardiac surgical procedures like coronary bypass surgery.

When Are Platelet Aggregation Tests Recommended?

Aggregation tests are usually done when affected individuals show clinical symptoms related to increased bleeding as well as signs associated with thrombus formation.

Symptoms Related to Bleeding Tendencies

• Bleeding from the nose (epistaxis).

• Prolonged bleeding from a minor cut.

• Heavy and long menstrual flow in women.

• Bleeding from gums (gingival bleeding).

• Blood in the urine (hematuria).

• Purple discoloration of the skin (petechiae).

Symptoms Related to Thrombus Formation

• Headaches.

• Weakness and generalized tiredness.

• Dizziness and fatigue.

• Numbness or tingling sensation in extremities (hands and legs).

• Throbbing pain or cramping in legs and hands.

• Redness and swelling in extremities.

• Difficulty in breathing.

How Is Platelet Aggregation Tested?

Evaluation of platelet aggregation is included in the panel of clotting tests which determines the capacity of platelets to form clots. Some of the essential diagnostic features of platelet aggregation are as follows -

• Initial screening blood tests show significantly increased bleeding time than the normal range.

• Failure to clump together in various platelet function tests indicates the absence of platelet aggregation.

• Platelet aggregometry is the most reliable approach for evaluating platelet aggregation.

• Here, platelets are exposed in suspension to various stimuli or platelet aggregation agonists such as thrombin, adenosine diphosphate (ADP), and thromboxane A2.

• Platelet-platelet adhesion interaction is estimated by real-time analysis.

• Flow cytometric analysis of surface proteins (GPIb and GPIIb-IIIa) shows reduced surface density in decreased platelet aggregation.

• Light transmission aggregometry assay analyzes the movement of platelets during aggregation.

• Ristocetin-induced platelet aggregation (RIPA) analysis is done to identify deficiency of vWF and integrin.

• The estimation of platelet aggregates (PAg) and the number of platelets per PAg particle is more sensitive than other methods of detecting platelet aggregation.

What Is the Clinical Significance of Platelet Aggregation?

Understanding platelet aggregation helps in preventing complications associated with its altered dysfunction. Some of its clinical implications are as follows -

• Platelet aggregation inhibitors deactivate enzymes such as thromboxane and are used in preventing clot formation in cardiac disorders such as myocardial infarction, following surgeries like coronary bypass and stenting.

• Dipyridamole, Aspirin, and Ticlopidine are antiplatelet drugs that are commonly used as prophylaxis to prevent stroke and ischemia.

• Platelet aggregation is widely affected by some common drugs such as non-steroidal anti-inflammatory drugs (Indomethacin and Naproxen), antidepressants, and antihistamines.

Conclusion

Platelet aggregation facilitates platelet plug formation at vascular injury sites, thus preventing severe bleeding complications. Over-aggregated platelets lead to life-threatening thrombotic disorders such as heart attack and stroke. Early detection and assessment of platelet aggregation tests help in reducing several complications.