**2.3.1 Platelet MP and coagulation**

Traditionally, platelets major function was thought to be due to their aggregability and ability to plug damaged endothelium and capillary vessels. More recently, they are thought to form an important substrate for the coagulation pathway with their membrane providing the surface for the formation of the prothrombinase complex (comprising the Xa and Va complex). This enzyme complex leads to conversion of fibrinogen to fibrin which in combination with a variety of other factors leads to a stable clot at the site of injury. The presence of platelet microparticles at the site of blood vessel injury may contribute to this process by providing a large source of surface membrane for assembly of the enzymatic process. Indeed the exposure of phosphotidylserine at the site of thrombin generation increases the enzymatic catalyic effect by several hundred fold (Aleman). Platelets thus appear to have two major physiological roles for achieving haemostasis - form a platelet plug at the site of endothelial injury and generate microparticles which provide a surface for activation of the coagulation cascade leading to formation of the fibrin clot. The third possible role for the platelet MP could possibly be in maintaining the integrity of normal resting endothelium (Cambien, 2004). This area is still being actively explored. The role of MP in haemostasis is illustrated in figure 1.

Apart from procoagulant function MP could also be involved in anticoagulant activity. Microparticles with TFPI (tissue factor pathway inhibitor) and antithrombin activity have been described (Morel*, et al* 2006, Siljander). However, the anticoagulant MP have not been as extensively studied and it would be interesting to evaluate these MP - its association with pathologic conditions.

Microparticles: Role in Haemostasis and Venous Thromboembolism 7

In an intact blood vessel tissue factor is usually restricted to adventitia and protected by the endothelial layer. However, small amounts of monocyte related tissue factor have been isolated in circulation (Key). The presence of tissue factor (TF) bearing microparticles, mainly derived from monocytes, in circulation has been shown to participate in initiation of fibrin polymerization (Eilertsen and Osterud 2004, Key). Although usually found to be in very small numbers in normal circulation, these increase dramatically at the site of injury. The interaction between tissue factor bearing MP and platelet MP is also of interest as there appears to be some evidence that they may be complementary in terms of thrombin

The evidence for the involvement of these MP in its various physiological roles in

The initial evidence for the role of MP in haemostasis comes from the cell based model. In this model plasma coagulation proteins are activated on the membrane surface after exposure to tissue factor. This leads to enzymatic cleavage of thrombin from prothrombin which ultimately converts fibrinogen to fibrin. This forms the fibrin clot and leads to haemostasis along with other components of the clot such as platelets and monocytes (Biro*,* 

Studies using intravital microscopy have shown that TF bearing MP derived from haemopoietic cells are incorporated into a thrombus. A laser injury model using the cremaster muscle arterioles of the mouse showed that MP participate in thrombosis (Falati*, et al* 2003). Although these studies visualize incorporation of TF bearing MP into the

These studies have involved introducing exogenous MP from patients or other source into animal models. In one such study MP from patients with acute coronary syndrome were introduced in to a rat model triggered venous thrombosis (Mallat*, et al* 2000). This study supports the role of TF bearing MP in promotion of VTE, However, the cellular sources of

Scott Syndrome is an extremely rare hemorrhagic disorder characterized by bleeding diathesis ( only three well documented cases of Scott syndrome have been reported to date) (Zwaal*, et al* 2004). The bleeding tendency is thought to be due to impaired procoagulant activity of stimulated platelets – the platelets being unable to expose anionic phospholipids and to shed procoagulant microparticles. The exposure of the aminophospholipids, mainly

thrombus, it is not yet known if these MP are actually functional.

this TF has not been entirely clarified in other studies (Shantsila*, et al*).

**2.4 Tissue factor bearing MP** 

generation potential (Key and Kwaan).

**2.5.1 Cell based haemostasis model** 

*et al* 2003, Chirinos*, et al* 2005).

**2.5.2 Live imaging model** 

**2.5.3 Animal models** 

**2.5.4 Scott Syndrome** 

haemostasis comes from the following models.

**2.5 Modelling MP in thrombosis** 

Fig. 1. The interaction of MP of platelet and monocyte origin being recruited in thrombus formation at site of endothelial injury.
