**2.5.3 Animal models**

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

#### **2.5.4 Scott Syndrome**

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

Microparticles: Role in Haemostasis and Venous Thromboembolism 9

case-control fashion. In those with circulating MP above the 90th percentile of the control population's distribution, a five fold increased risk was observed (Bucciarelli, 2011). They found that elevated MP were indeed an independent risk factor for VTE and this warrants a

The draw back of the studies in this area of VTE include the variability of type of MP studied, the techniques employed for measurement of MP and retrospective nature of

In contrast to idiopathic VTE, there is strong evidence for involvement of MP in thrombogeneticity in patients with underlying immune disorders. Important examples include antiphospholipid antibody syndrome and heparin induced thrombocytopaenia with thrombosis syndromes (Combes*, et al* 1999, Dignat-George*, et al* 2004, Walenga*, et al* 2000). Markedly elevated platelet derived MP have been desccribed in both clinical syndromes (Hughes, 2000). There is experimental evidence to suggest that circulating autoantibodies trigger the formation of excess MP contributing to the prothrombotic process in these patients. Circulating MP in these syndromes have been shown to expose GPIb,GPIIbIIIa, P-

In contrast to the above discussion for idiopathic VTE – thrombosis, cancer and microparticles seem to have a more definitive relationship. The MP are thought to reflect a balance between cell stimulation, proliferation and death which may be important in cancer related thrombosis. Cancer increases the risk of VTE by four fold and addition of chemotherapy further increases the risk by six to eight fold (Furie and Furie 2006). It is possible that circulating MP shed from cancer cells represent an indication for tumours to metastasize in the absence of any other clinical evidence for metastasis. A recent report states that platelet MP markedly stimulated the metastatic potential of 5 different cancer cell lines (Rak). It has also been shown that human tumor derived MP when injected into mice

Procoagulant properties of tumor cell MP have been an area of intense study. A range of endothelial, monocyte and leukocyte MP along with tissue factor bearing MP appear to have a coagulant potential and have shown to be elevated in various such as cancers such as

A recent in vivo live microscopy mouse model with pancreatic cancer demonstrated that TF bearing MP released from the cancer cells entered circulation and participated in the

The most important evidence for role of MP in VTE and cancer comes from clinical studies showing increased numbers and procoagulant activity of MP in cancer (Langer). Elevated levels of tissue factor bearing MP were associated with VTE events in those with advanced malignancy particularly pancreatic cancer. The microparticle levels in cancer patients also predicted the development of thrombosis, with the one year estimate of those with TF

selectin and thrombospondin all of which help promote thrombosis (Jy*, et al* 2007).

activated coagulation by virtue of their TF procoagulant activity (Thaler).

pancreatic, breast and prostate (Pilzer*, et al* 2005, Simak and Gelderman 2006).

thrombus formation at a distant site (Thomas, 2009).

confirmation in a prospective cohort study.

**3.1.3 Microparticles, VTE and cancer** 

investigations undertaken.

**3.1.2 Immune related VTE** 

phosphatidylserine, on surface of stimulated platelets or derived microparticles, is critical for the formation of enzyme complexes in the clotting process (Zwaal*, et al* 2004, Zwaal*, et al* 2005). Mutations involving the ABCA1 ATP transporter have been reported in this syndrome (Zwaal*, et al* 2004).

There are several other mechanisms by which MP influence the endovascular system. They may modulate endothelial function and carry proangiogeneic molecules (Lozito and Tuan). Recently MP bearing Sonic hedgehog have been shown modulate angiogenesis (Soleti*, et al* 2009, Soleti and Martinez 2009). They may also serve as novel carriers for transport of genetic material – such as mRNA or microRNA and these are currently areas of intense research (Rak).
