Good day,
I have a bit of a detailed issue with reasoning logically why Platelet Aggregation Inhibitors (PAI’s) are more effective than Anticoagulants (AC’s) in atherosclerosis.
I do understand that the basis of initiating a thrombus in atherosclerosis is mainly the activation and aggregation of platelets because of vessel wall damage, but there are effects in AC’s that also inhibit platelet activation and aggregation; through the inhibition of Thrombin. Furthermore, aggregation by vessel wall damage is not so effective in the absence of Thrombin which is caused by AC's (explained below). Here’s what I have understood from reading several sources.
Platelet Aggregation Inhibitors
PAI’s inhibit the production and response of Thromboxane 2 (TXA2) and Adenosinephosphate (ADP) in platelets. Therefore, it inhibits platelet activation and aggregation.
They also therefore inhibit the activation of the Intrinsic pathway through Factor XII which is normally activated by platelet activation to produce Thrombin (1). However, Factor XIIa is a very small contributor to Thrombin formation. This is proven by the fact that patients with XII deficiency do not have increased bleeding risks. In fact, the other factors of the Intrinsic pathway are mainly activated by Thrombin itself and the Intrinsic cascade is therefore almost completely dependent on Thrombin production by the Extrinsic cascade.
There is still platelet activation and aggregation through binding to the damaged vessel wall and through Thrombin production. Thrombin is the strongest contributor to platelet aggregation (2). And there is still activation of both the Intrinsic and Extrinsic coagulation cascades and thus Fibrin production, which helps maintaining aggregation by these causes.
Anticoagulants
AC’s inhibit the production of Thrombin, and therefore Fibrin, of both the Intrinsic and Extrinsic Coagulation cascades. This is because AC’s inhibit factors that are at the end of both cascades. Inhibiting Thrombin also inhibits platelet activation and aggregation, and is furthermore the strongest contributor to platelet aggregation (2).
There is still platelet activation and aggregation through the damaged vessel wall and TXA2/ADP. However, since there is less Fibrin production because of Thrombin inhibition, aggregation of platelets by these other causes would only last a few hours. The reason is that aggregation occurs by multiple platelets attaching to Fibrinogen strands but Fibrinogen is water soluble. Converting Fibrinogen to the insoluble Fibrin by Thrombin is neccessary for strengthening and maintaining aggregation for clot formation. Aggregation through TXA2/ADP and the damaged vessel wall are therefore not so effective when AC’s are given.
(1): Polyphosphates: a link between platelet activation, intrinsic coagulation and inflammation?
(2): Platelets in Thrombotic and Non-Thrombotic Disorders: Pathophysiology, Pharmacology and Therapeutics
Conclusion
Reading and comparing the effects of PAI’s and AC’s, I would say that AC’s should be more effective in atherosclerosis, since it (a) inhibits both coagulation cascades as well as (b) inhibiting a strong contributor to platelet activation and aggregation (Thrombin inhibition). Aggregation by other causes are made ineffective since there is less Fibrin. You would basically be left with a clot only consisting of platelets that are attached to the damaged vessel wall.
PAI’s on the other hand only (a) inhibit platelet activation and aggregation through TXA2 and ADP. They also inhibit Thrombin production through Factor XII activation, but this is neglectable. Aggregation and activation through the damaged vessel wall and Thrombin are still there as well as Fibrin production that maintains these causes of aggregation. You would be left with a clot that consists of aggregated platelets caused by vessel wall damage and Thrombin, maintained by Fibrin produced through the coagulation cascades.
What is the exact extra property that I’m missing that makes PAI’s more effective than AC’s in atherosclerosis? Is it truly more effective than PAI's but substituted by PAI's merely because of the larger bleeding risk?
I have a bit of a detailed issue with reasoning logically why Platelet Aggregation Inhibitors (PAI’s) are more effective than Anticoagulants (AC’s) in atherosclerosis.
I do understand that the basis of initiating a thrombus in atherosclerosis is mainly the activation and aggregation of platelets because of vessel wall damage, but there are effects in AC’s that also inhibit platelet activation and aggregation; through the inhibition of Thrombin. Furthermore, aggregation by vessel wall damage is not so effective in the absence of Thrombin which is caused by AC's (explained below). Here’s what I have understood from reading several sources.
Platelet Aggregation Inhibitors
PAI’s inhibit the production and response of Thromboxane 2 (TXA2) and Adenosinephosphate (ADP) in platelets. Therefore, it inhibits platelet activation and aggregation.
They also therefore inhibit the activation of the Intrinsic pathway through Factor XII which is normally activated by platelet activation to produce Thrombin (1). However, Factor XIIa is a very small contributor to Thrombin formation. This is proven by the fact that patients with XII deficiency do not have increased bleeding risks. In fact, the other factors of the Intrinsic pathway are mainly activated by Thrombin itself and the Intrinsic cascade is therefore almost completely dependent on Thrombin production by the Extrinsic cascade.
There is still platelet activation and aggregation through binding to the damaged vessel wall and through Thrombin production. Thrombin is the strongest contributor to platelet aggregation (2). And there is still activation of both the Intrinsic and Extrinsic coagulation cascades and thus Fibrin production, which helps maintaining aggregation by these causes.
Anticoagulants
AC’s inhibit the production of Thrombin, and therefore Fibrin, of both the Intrinsic and Extrinsic Coagulation cascades. This is because AC’s inhibit factors that are at the end of both cascades. Inhibiting Thrombin also inhibits platelet activation and aggregation, and is furthermore the strongest contributor to platelet aggregation (2).
There is still platelet activation and aggregation through the damaged vessel wall and TXA2/ADP. However, since there is less Fibrin production because of Thrombin inhibition, aggregation of platelets by these other causes would only last a few hours. The reason is that aggregation occurs by multiple platelets attaching to Fibrinogen strands but Fibrinogen is water soluble. Converting Fibrinogen to the insoluble Fibrin by Thrombin is neccessary for strengthening and maintaining aggregation for clot formation. Aggregation through TXA2/ADP and the damaged vessel wall are therefore not so effective when AC’s are given.
(1): Polyphosphates: a link between platelet activation, intrinsic coagulation and inflammation?
(2): Platelets in Thrombotic and Non-Thrombotic Disorders: Pathophysiology, Pharmacology and Therapeutics
Conclusion
Reading and comparing the effects of PAI’s and AC’s, I would say that AC’s should be more effective in atherosclerosis, since it (a) inhibits both coagulation cascades as well as (b) inhibiting a strong contributor to platelet activation and aggregation (Thrombin inhibition). Aggregation by other causes are made ineffective since there is less Fibrin. You would basically be left with a clot only consisting of platelets that are attached to the damaged vessel wall.
PAI’s on the other hand only (a) inhibit platelet activation and aggregation through TXA2 and ADP. They also inhibit Thrombin production through Factor XII activation, but this is neglectable. Aggregation and activation through the damaged vessel wall and Thrombin are still there as well as Fibrin production that maintains these causes of aggregation. You would be left with a clot that consists of aggregated platelets caused by vessel wall damage and Thrombin, maintained by Fibrin produced through the coagulation cascades.
What is the exact extra property that I’m missing that makes PAI’s more effective than AC’s in atherosclerosis? Is it truly more effective than PAI's but substituted by PAI's merely because of the larger bleeding risk?
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