**2.1 Pathophysiology of the coagulation mechanism**

Under normal conditions, the blood circulates freely within the vascular system. However, when blood escapes to extravascular sites after blood vessel injury or it becomes pathologically challenged, haemostasis may be activated ending in the formation of blood (fibrin) clot. This process is finely regulated by positive and negative feedback loops that control fibrin clot formation .

For many decades the accepted blood coagulation mechanism has been based on the concept of the coagulation cascade model that describes the interactions of the coagulation factors along two pathways: the intrinsic pathway which is triggered by the contact of blood with a foreign surface, and the extrinsic pathway which is triggered by exposure of the blood to the transmembrane receptor tissue factor (TF) which binds to clotting factor VIIa to form TF/FVIIa complex. Both pathways meet at the level of clotting factor X after which the common pathway progresses until the generation of the thrombin and the formation of fibrin clot. However, while the cascade model delineates the interactions between the coagulation proteins and provides a framework for interpreting the common screening coagulation tests (particularly the PT and the APTT), it is gradually been realized that the cascade model suffers from many limitations, as it fails to explain convincingly how hemostatic activation occurs *in vivo*. For example, this model cannot explain why hemophiliacs bleed when they have an intact factor VIIa/TF "extrinsic" pathway.

Fig. 1. Cell-based model of the mechanism of blood coagulation

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 the intrinsic pathway, playing an amplification role.

## **2.2 The role extrinsic pathway in thrombosis**

100 Deep Vein Thrombosis

Under normal conditions, the blood circulates freely within the vascular system. However, when blood escapes to extravascular sites after blood vessel injury or it becomes pathologically challenged, haemostasis may be activated ending in the formation of blood (fibrin) clot. This process is finely regulated by positive and negative feedback loops that

For many decades the accepted blood coagulation mechanism has been based on the concept of the coagulation cascade model that describes the interactions of the coagulation factors along two pathways: the intrinsic pathway which is triggered by the contact of blood with a foreign surface, and the extrinsic pathway which is triggered by exposure of the blood to the transmembrane receptor tissue factor (TF) which binds to clotting factor VIIa to form TF/FVIIa complex. Both pathways meet at the level of clotting factor X after which the common pathway progresses until the generation of the thrombin and the formation of fibrin clot. However, while the cascade model delineates the interactions between the coagulation proteins and provides a framework for interpreting the common screening coagulation tests (particularly the PT and the APTT), it is gradually been realized that the cascade model suffers from many limitations, as it fails to explain convincingly how hemostatic activation occurs *in vivo*. For example, this model cannot explain why

hemophiliacs bleed when they have an intact factor VIIa/TF "extrinsic" pathway.

**Prothrombin**

**Activated platelets**

**Propagation**

**Prothrombin Xa IXa XIa**

**Thrombin**

**2.1 Pathophysiology of the coagulation mechanism** 

control fibrin clot formation .

**Platelet**

**Fibroblast**

**Thrombin**

**VIIa**

**Initiation**

**Xa**

**IXa TF**

**VIIIa XIa**

Fig. 1. Cell-based model of the mechanism of blood coagulation

**Amplification**

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 al., 2007).

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

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

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 becomes increasingly precarious as protein synthetic capacity is lost .

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

Emerging Issues in Deep Vein Thrombosis; (DVT) in Liver Disease and in Developing Countries 103

Diagnosing DVT in patients with liver disease need high level suspicion, presence of laboratory investigation such as D-dimer and radiological procedure of Duplex ultrasound; thus elevation of coagulation markers such as the prothrombin time and partial thromboplastin time does not safeguard against thrombotic events. Serum albumin level was independently associated with

Current guidelines from American College of Chest Physicians (ACCP) DVT prophylaxis do not specifically comment on the advanced liver disease patients' population (Senzolo et al., 2009). The lack of specific guidelines is because of the perceived risk of bleeding complications, sense of auto-anticoagulation, impaired laboratory tests, and most important lack of clinical trials to support the practice of routine use of DVT prophylaxis in liver disease/cirrhosis and its safety, particularly the risk of bleeding is unknown. Recently two studies (Senzolo et al., 2009, Bechman et al .,2010).) found that the prophylactic use of LMWH in patients with cirrhosis and who are at high risk of thrombosis, to be safe from the risk of bleeding. Actually Bechman et al .,2010 revealed for the first time, to our knowledge, there are apparent decreased efficacy of LMWH in cirrhotic patients, which may indeed

argue for studying the appropriate dosing in cirrhotic patients (Bechman et al., 2010).

(Abdulaziz et al., 2011). The utilization of DVT prophylaxis was suboptimal.

**3. Deep vein thrombosis in developing countries** 

estimates put costs at nearly \$500 million per year (Hawkins, 2004).

**3.1 Scale of DVT problem in the developing countries** 

In a recent study, approximately 76% of the cirrhotic patients included in the cohort received neither pharmacological nor mechanical DVT prophylaxis. No significant differences in the incidence of VTE were observed between the group that received pharmacologic or mechanical prophylaxis and the group that did not receive prophylaxis

Until the risks and benefits of VTE prophylaxis are established in this particular population, the VTE prophylaxis cannot be withdrawn in the cirrhotic population at present time.

Deep vein thrombosis is a preventable disease and the incidence of VTE is 1-3 per 100 per year (Nordstrőm et al., 1992; Anderson et al., 1991; Oger et al., 2000; Cushman et al., 2004, ). DVT is a significant cause of morbidity and mortality and without prophylaxis, the risk of a DVT event is especially high in patients admitted to medical orthopedic surgery wards (Geerts et al., 2008), with an incidence of venographic DVT without prophylaxis estimated at 40% to 60% (Geerts et al., 2008). Given its silent nature; the incidence, prevalence, morbidity and mortality rates of DVT are probably under-estimated in developing countries. Although most patients survive DVT, yet serious and costly long-term complications may occur; almost one-third of patients will suffer from venous stasis syndrome (postphlebitic syndrome) (Prandoni et al., 1996). DVT is a major burden on US healthcare systems:

DVT in developed counties is considered a public health problem and over the years this has led to elaboration of numerous strategies directed towards reducing the risks of DVT.

the occurrence of thrombosis (Ben Ari et al., 1997, Senzolo et al., 2009).

**2.6 Diagnostic and treatment challenges** 

**2.7 DVT prophylaxis in liver disease** 

(Senzolo et al., 2009).

mesenteric systems (Mammen et al., 1992), hepatic veins (Singh et al., 2000), and peripherally in the extremities with associated pulmonary emboli (Northup et al., 2006). The prothrombotic state may be involved in other sequelae of chronic liver disease, including hepatic parenchymal extinction, fibrosis and portopulmonary hypertension. Thus, a prolonged prothrombin time does not adequately portray the levels of other clotting factors, particularly factors VIII, X and II that can be more than adequate to promote clot formation (Violi et al., 1995). As well, it is known that the coagulation disorders associated with falling liver can induce further hepatic damage, namely, parenchymal extinction. Wanless et al (Wanless et al., 1995) have clearly demonstrated the histopathologic evidence of the secondary hepatic damage caused by circulatory disturbances due to thrombotic occlusion of intrahepatic blood vessels (microvascular thrombosis).
