**3. Activation of coagulation cascade and fibrinolysis**

Symptomatic atherothrombotic events such as acute myocardial infarction occur when organ perfusing arterial branch was occluded by thrombi. The diameter of organ perfusing vessels is substantially larger than a single cell of platelet. Indeed, the diameter of platelets is just 2–5 μm, while the diameter of myocardial perfusing coronary arterial branches is 2–3 mm. The size of vessel diameter is typically 1000 more than the size of platelet diameter. It is nonrealistic to imagine that coronary arterial branches were occluded by platelet thrombi. Indeed, when coronary arterial thrombi causing myocardial infarction are aspirated by thrombo-aspiration therapy, the main component of occlusive thrombi was fibrin (**Figure 3**). It is

#### **Figure 3.**

*Major components of thrombi causing acute myocardial infarction. Sample thrombi were aspirated from patients with acute myocardial infarction. The main results and study protocols were published elsewhere [53]. Here, electron microscopy results are shown. Fibrin fibrils could be seen around activated platelets (arrow).*

**61**

**Figure 4.**

*Mechanism of Thrombus Formation in Regard to Diet DOI: http://dx.doi.org/10.5772/intechopen.92382*

noteworthy that fibrin fibrils are detected around activated platelets (**Figure 3** is the

The lipid components of activated platelet changed from the ones at the quiescent state. Negatively charged phospholipids appeared on the surface of activated platelets [22]. Then, various coagulation factors accumulated around the lipid to form prothrombin complex. On the activated platelet, thrombin generation occurs extremely efficiently. Indeed, thrombin generation rate in the absence of activated platelet and tissue factor is almost 0 as compared to that in its presence. At the site of atheroma rupture, large enough fibrin thrombi were formed as a result of the accumulation of activated platelet and exposure of tissue factor from the ruptured atheroma. Tissue factor accumulated in the atheroma is generated from inflammatory cells, which migrated into the atheroma. In the animal study, dietary lipid restriction reduces the amount of tissue factor accumulated in the atheroma [30]. The clinical factor of the reduction of the onset of myocardial infarction by the use of lipid-lowering therapy [31] may be related to reduction of lipid accumulation and subsequent reduction in tissue factor accumulated in the atheroma. Moreover, there are several publications indicating the impact of food intake for the lipid component of blood cells [23, 24]. The rate of fibrin formation at the site of endothelial damage and platelet accumulation should be modified by food from both activated platelet-derived procoagulant

product in collaboration with Prof. Yujiro Asada at Miyazaki University).

activity and the amount of tissue factors accumulated in the atheroma.

The process of thrombus formation at the site of endothelial injury is complex. We have attempted to develop the process model of thrombus formation as shown in **Figure 4** [32]. The model is still simple but includes various physically and chemically different events. First, the model implemented the effect of blood flow, which is a purely physical phenomenon. Second, the model includes platelet

*Coupling model of blood flow, platelet, coagulation, and fibrinolysis. Thrombus formation at the site of endothelial injury is modeled. Nonactivated platelets (NP) adhered at the site of endothelial injury through von Willebrand factor (VWF) and collagen are exposed there. NP become activated platelets (AP) by their interaction with VWF/collagen (①). AP has a potential to convert prothrombin to thrombin on their membrane surface (②). After production of thrombin from prothrombin (③), thrombin converts soluble fibrinogen to fibrin thrombi. (④) thrombin also has a function to further activate platelets through thrombin receptor stimulation. (⑤) Fibrinolytic system is also incorporated in this model. Functional endothelial cells constitutively release both tissue-type plasminogen activator (t-PA: ⑥) and plasminogen activator inhibitor (PAI)-1 (⑦). T-PA converts plasminogen to plasmin, which has fibrinolytic activity (⑧) unless inactivated by binding with PAI-1. Plasmin is a strong enzyme able to degrade fibrin. Its function is immediately neutralized* 

*by its binding with a2-plasmin inhibitor to form plasmin a2-plasmin inhibitor complex (PIC: ⑨).*

#### *Mechanism of Thrombus Formation in Regard to Diet DOI: http://dx.doi.org/10.5772/intechopen.92382*

*New Insights into Metabolic Syndrome*

platelet adhesion at the site of endothelial injury.

cholesterol intake and the risk of atherothrombotic event risk.

**3. Activation of coagulation cascade and fibrinolysis**

It is of particular importance that endothelial damage is not caused only by acute physical or chemical stimulation. In the recent era, human beings enjoy longer life than those who lived hundreds of years ago. Just like carrying human being, vessel system become old when people become old. Longer time exposure of vessel wall to atherogenic lipids such as LDL cholesterol and its related local biological reaction causes atherosclerosis [27, 28]. Antithrombotic potential of endothelial cell in patients with atherosclerosis is reduced when compared to younger normal ones. Moreover, plaque rupture exposes subendothelial thrombotic materials to vessel lumen. Thus, atherothrombotic events occur frequently [29] in the era of aging society. The initial event resulting in symptomatic atherothrombosis is always

By understanding the mechanism of atherosclerosis and atherothrombosis, it is rather easy to understand that various types of food intake influence the risk of thrombosis. As regards nutritional factor, there is a hot discussion concerning cholesterol. Some suggested potential benefit of cholesterol restriction for prevention of atherothrombosis. The other suggest there are no relationship between daily

Symptomatic atherothrombotic events such as acute myocardial infarction occur when organ perfusing arterial branch was occluded by thrombi. The diameter of organ perfusing vessels is substantially larger than a single cell of platelet. Indeed, the diameter of platelets is just 2–5 μm, while the diameter of myocardial perfusing coronary arterial branches is 2–3 mm. The size of vessel diameter is typically 1000 more than the size of platelet diameter. It is nonrealistic to imagine that coronary arterial branches were occluded by platelet thrombi. Indeed, when coronary arterial thrombi causing myocardial infarction are aspirated by thrombo-aspiration therapy, the main component of occlusive thrombi was fibrin (**Figure 3**). It is

*Major components of thrombi causing acute myocardial infarction. Sample thrombi were aspirated from patients with acute myocardial infarction. The main results and study protocols were published elsewhere [53]. Here, electron microscopy results are shown. Fibrin fibrils could be seen around activated platelets (arrow).*

**60**

**Figure 3.**

noteworthy that fibrin fibrils are detected around activated platelets (**Figure 3** is the product in collaboration with Prof. Yujiro Asada at Miyazaki University).

The lipid components of activated platelet changed from the ones at the quiescent state. Negatively charged phospholipids appeared on the surface of activated platelets [22]. Then, various coagulation factors accumulated around the lipid to form prothrombin complex. On the activated platelet, thrombin generation occurs extremely efficiently. Indeed, thrombin generation rate in the absence of activated platelet and tissue factor is almost 0 as compared to that in its presence. At the site of atheroma rupture, large enough fibrin thrombi were formed as a result of the accumulation of activated platelet and exposure of tissue factor from the ruptured atheroma. Tissue factor accumulated in the atheroma is generated from inflammatory cells, which migrated into the atheroma. In the animal study, dietary lipid restriction reduces the amount of tissue factor accumulated in the atheroma [30]. The clinical factor of the reduction of the onset of myocardial infarction by the use of lipid-lowering therapy [31] may be related to reduction of lipid accumulation and subsequent reduction in tissue factor accumulated in the atheroma. Moreover, there are several publications indicating the impact of food intake for the lipid component of blood cells [23, 24]. The rate of fibrin formation at the site of endothelial damage and platelet accumulation should be modified by food from both activated platelet-derived procoagulant activity and the amount of tissue factors accumulated in the atheroma.

The process of thrombus formation at the site of endothelial injury is complex. We have attempted to develop the process model of thrombus formation as shown in **Figure 4** [32]. The model is still simple but includes various physically and chemically different events. First, the model implemented the effect of blood flow, which is a purely physical phenomenon. Second, the model includes platelet

#### **Figure 4.**

*Coupling model of blood flow, platelet, coagulation, and fibrinolysis. Thrombus formation at the site of endothelial injury is modeled. Nonactivated platelets (NP) adhered at the site of endothelial injury through von Willebrand factor (VWF) and collagen are exposed there. NP become activated platelets (AP) by their interaction with VWF/collagen (①). AP has a potential to convert prothrombin to thrombin on their membrane surface (②). After production of thrombin from prothrombin (③), thrombin converts soluble fibrinogen to fibrin thrombi. (④) thrombin also has a function to further activate platelets through thrombin receptor stimulation. (⑤) Fibrinolytic system is also incorporated in this model. Functional endothelial cells constitutively release both tissue-type plasminogen activator (t-PA: ⑥) and plasminogen activator inhibitor (PAI)-1 (⑦). T-PA converts plasminogen to plasmin, which has fibrinolytic activity (⑧) unless inactivated by binding with PAI-1. Plasmin is a strong enzyme able to degrade fibrin. Its function is immediately neutralized by its binding with a2-plasmin inhibitor to form plasmin a2-plasmin inhibitor complex (PIC: ⑨).*

adhesion and activation. Platelet adhesion is implemented to be medicated by its GPIbα binding with von Willebrand factor (VWF) (① in **Figure 4**). GPIbα binding with VWF is a chemical phenomenon, but the binding force is a physical one. We have implemented both in the same model. Platelets were implemented to be activated to change their biological roles (② in **Figure 4**). This process is a biological process. The detailed process model of platelet activation was published elsewhere [33]. Briefly, platelets were settled to be captured by VWF under blood flow condition. Collagen exposed at the site of endothelial injury also interacts with platelet and contributed to platelet activation through its receptor, namely, GPVI [34]. Then, activated platelet was settled to have stronger capacity to bind with injured vessel wall, cohesion each other, and possess the capacity to express coagulogenic phospholipids. Then, prothrombin conversion to thrombin was settled to occur only on the surface of activated platelets (③ in **Figure 4**). Thrombin function is neutralized promptly by its interaction with antithrombin III. Thrombin implemented to have function to convert fibrinogen to fibrin (④ in **Figure 4**) and further activated platelet through thrombin receptor stimulations [35].

There are several coagulation factors, the function of which is regulated strongly by food intake. Gla-domain of coagulation factors plays crucial roles in the accumulation of coagulation factors around exposed negatively charged phospholipids on activated platelets [36]. Gla-domain also plays crucial roles for enzymatic function of coagulation factors. Carboxylation of Gla-domain is mediated by vitamin K. Thus, coagulation cascade does not work well in the absence of vitamin K or in patients taking vitamin K inhibitor. It is noteworthy that there are many foods including fermented food that are known to contain abundant vitamin K. Strict food restriction is necessary to keep the anticoagulant effects of vitamin K inhibitors. Recently, a larger load of vitamin K on health is cautioned [37].

The amount of fibrin formed at the site of endothelial injury was reduced by the effect of intrinsic fibrinolysis. Fibrinolysis is a complex pathway, but the details of which is simplified to be incorporated as shown in **Figure 4**. Vascular endothelial cells have balanced roles for fibrinolysis by releasing both fibrinolytic tissue-type plasminogen activator (t-PA: ⑥) and the one has antifibrinolytic effects of plasminogen activator inhibitor (PAI)-1 (⑦). Both of them are constitutively released from endothelial cells. But the rates of their releases were individually controlled in individual endothelial cells. When the rate of t-PA release increases, the amount of fibrin formed around the endothelial cells becomes smaller. It becomes larger in the case when the rate of PAI-1 release increases. Free t-PA has a potential to convert plasminogen to plasmin. (⑧) Plasmin is a strong protease, which can dissolve many functional proteins including fibrinogen. To avoid too much protein degradation, activity of plasmin is promptly neutralized by the function of α2-plasmin inhibitor (α2-PI: ⑨).

Previous publication suggested increased PAI-1 release after acute myocardial infarction and its role for the increased recurrence of myocardial infarction [38]. Animal experiments revealed that the food coloring agent of crocin reduces activity of PAI-1 and prevents thrombosis [39]. In human, increased PAI-1 activity is reported at the time of too much intake of fat [40]. Total fibrinolytic activity in humans is also reported to be low in obese patients [41]. Decreased fibrinolytic activity in patients taking too much lipid is one potential reason of increased risk of thrombosis in these patients.
