Atherothrombosis

Question 1

Question 1:
Define hemostasis and thrombosis. How does Virchow’s Triad explain the development of thrombosis?

Answer 1

Model Answer:
* Hemostasis is the physiological process that stops bleeding after vascular injury, involving vasoconstriction, platelet plug formation, and fibrin clot reinforcement.
* Thrombosis is the pathological formation of a clot inside a blood vessel, obstructing blood flow.
* Virchow’s Triad outlines three factors promoting thrombosis:
1. Vessel wall injury (e.g., endothelial dysfunction),
2. Abnormal blood flow (stasis or turbulence),
3. Abnormal blood constituents (e.g., hypercoagulability, platelet activation).

Question 2

Question 2:
List the key surface receptors on platelets involved in hemostasis and describe their binding targets.

Answer 2

Model Answer:
* GPVI: binds collagen at injured vessel sites.
* GPIb-IX-V complex: binds von Willebrand Factor (VWF).
* αIIbβ3 (GPIIbIIIa): binds fibrinogen, mediates platelet aggregation.
* P-selectin: binds PSGL-1 on leukocytes, facilitating leukocyte recruitment.

Question 3

Question 3:
Compare and contrast arterial and venous thrombosis based on flow characteristics, thrombus composition, and clinical manifestations.

Answer 3

Model Answer:
* Arterial Thrombosis:
o High shear flow, common in stenotic arteries.
o Platelet-rich (“white”) thrombi.
o Causes ischemic events like myocardial infarction and stroke.
* Venous Thrombosis:
o Low shear/stasis, especially around venous valves.
o Fibrin and red blood cell-rich (“red”) thrombi.
o Causes deep vein thrombosis and pulmonary embolism.

Question 4

Question 4:
Explain how disturbed blood flow contributes to atherothrombosis, highlighting the roles of VWF and platelet activation.

Answer 4

Model Answer:
* Disturbed flow (from atherosclerotic stenosis) creates high shear gradients.
* VWF unfolds under high shear, exposing binding sites (A1 domain) for platelets.
* Platelets bind unfolded VWF via GPIb-IX-V and become activated.
* Shear-sensitive pathways involving PI3Kβ and PI3KC2α mediate further platelet activation.
* Accumulated platelets and coagulation factors in vortex regions promote thrombus formation.

Question 5

Question 5:
Describe the therapeutic strategies for treating arterial thrombosis and how they target different aspects of thrombus formation.

Answer 5

Model Answer:
* Thrombolysis: Intravenous tissue plasminogen activator (tPA) breaks down fibrin clots; must be given within a short window (~4.5 hours).
* Mechanical thrombectomy: Physically removes the clot using catheters.
* Anti-platelet drugs:
o P2Y12 receptor inhibitors (e.g., clopidogrel) block ADP-mediated platelet activation.
o Aspirin inhibits thromboxane A2 production, reducing platelet aggregation.
* Targeted therapies aim to prevent platelet activation while minimizing bleeding risk.

Question 6

Question 6:
A patient suffers a myocardial infarction due to atherothrombosis. Explain how shear stress and platelet signaling pathways contributed to thrombus formation.

Answer 6

Model Answer:
* Atherosclerotic plaque created a stenosis, causing high shear stress.
* VWF unfolded, anchoring to the damaged endothelium and forming ultra-long strings.
* Platelets bound to VWF via GPIb-IX-V, triggering shear-specific intracellular signaling via PI3Kβ.
* Platelet aggregation and coagulation factor accumulation led to occlusive thrombus formation.

Question 7

Question 7:
Why is blocking the αIIbβ3 integrin (GPIIbIIIa) a powerful but risky strategy in anti-thrombotic therapy?

Answer 7

Model Answer:
* αIIbβ3 integrin is critical for platelet-platelet aggregation via fibrinogen binding.
* Blocking it prevents virtually all platelet aggregation, significantly reducing thrombosis risk.
* However, it severely compromises hemostasis, increasing bleeding risk, making it suitable only for high-risk clinical scenarios.

Question 8

Question 8:
Discuss the dual role of platelet microparticles in vascular biology and disease.

Answer 8

Model Answer:
* Positive roles:
o Support angiogenesis by promoting endothelial repair.
o Seal microvascular lesions by aiding endothelial barrier function.
* Negative roles:
o Pro-thrombotic and pro-inflammatory, facilitating coagulation and leukocyte activation.
o Prometastatic in cancer, helping tumor cells evade immune detection.