**2. Deep vein thrombosis in liver disease**

Chronic liver diseases in the United States account for 400,000 hospitalizations and 27,000 deaths (Kochanek et al., 2004, Kozak et al. 2005). This area needs to be revisited with respect to DVT in liver disease, where viral liver disease is more common in developing countries than in developed countries (Williams,2006.). Patients with advanced liver disease (a failing liver) display a complexity of haemostatic abnormalities often occurring concurrently including coagulopathic, hypercoagulable, and hyperfibrinolytic disorders and increased platelet activation. Recent literature has revealed that hypercoagulability plays an important role in many aspects of acute and chronic liver disease (Nieuwdrop et al .2005, 2004). The resulting clinical state is determined by which component of these complex haemostatic mechanisms predominates.

Emerging Issues in Deep Vein Thrombosis; (DVT) in Liver Disease and in Developing Countries 101

The classical cascade model of the coagulation cascade is being replaced by the new, cellbased model of coagulation (Roberts et al.,2006 ) (Fig. 1), which emphasizes the interaction of coagulation proteins with cell surfaces of platelets, subendothelial cells and the endothelium. According to this model the coagulation is initiated (The Initiation Phase) by the formation of a complex between tissue factor (TF) exposed on the surface of fibroblasts as a result of a vessel wall injury, and activated factor VII (FVIIa), normally present in the circulating blood. The TF-FVIIa complexes convert FX to FXa on the TF bearing fibroblasts. FXa then activates prothrombin (FII) to thrombin (FIIa). The next phase is the Amplification Phase in which this limited amount of thrombin activates FVIII, FV, FXI and platelets, on the surface of blood platelets. Thrombin-activated platelets change shape, and as a result will expose negatively charged membrane phospholipids, which form the perfect template for the assembly of various clotting factors and full thrombin generation involving FVIIIa and FIXa (The Propagation Phase). According to this cell-based model the tissue factor (TF) extrinsic pathway is the principal cellular initiator of normal blood coagulation in vivo (Mackman et al. 2007 ), and the major regulator of haemostasis and thrombogenesis, with

From the above account, it is clear for clotting to occur blood must be exposed to tissue factor. Therefore for thrombosis to set such exposure will happen when the blood vessel is injured and blood comes in contact with variety of cells that express TF, in particular monocytes and neutrophils. Endothelial cells also express TF mostly due to binding TFexpressing microparticles (MPs- see below) (Schwertz et al. 2006). More prominence has recently been given circulating TF-positive microparticles (MPs) (Morel et al. 2006). These are small membrane fragments released from activated or apoptotic vascular cells (Rauch et

There is strong evidence to show that TF-positive MPs contribute to thrombosis in patients with cancer ( Rauch et al.,2007, Tesselaar et al.,2007), cardiovascular disease (Misumi et al., 1998), and sickle cell disease (Shet et al., 2003)*.* Many cell types can generate circulating TFpositive MPs including leucocytes, endothelial cells, platelets and vascular smooth muscles and these MPs can be recruited to a thrombus and enhance its growth in both arterial and

In case of severe liver disease the protein levels that are synthesized in the liver are reduced as the synthetic capacity is lost. Thus, levels of both pro-and anticoagulant proteins decrease as liver disease progresses. A relatively balanced reduction in pro-and anticoagulant activity does not result in a net hyper-or hypocoagulable state until the loss of liver synthetic capacity is severe. However, the ability of the haemostatic system to maintain haemostasis when stressed is progressively reduced. Thus, the balance between bleeding and thrombosis

In addition, the important role of endothelial function in maintaining haemostatic balance means that local endothelial dysfunction can lead to the development of a hypercoagulable state at one anatomic site. Thrombotic complications can be seen in the portal and

the intrinsic pathway, playing an amplification role.

**2.2 The role extrinsic pathway in thrombosis** 

venous thrombosis (Schwertz et al. 2006)*.*

**2.3 Pathophysiology of coagulation mechanism in liver disease** 

becomes increasingly precarious as protein synthetic capacity is lost .

al., 2007).
