Preface

The venous thrombosis care and profession has evolved considerably over the past 20 years. This book reflects the current practice, both technical and professional, of physicians from different fields. Venous thromboembolism became treatable with the discovery of heparin at the beginning of the 20th century. The presence of an effective therapy increased the importance of diagnosing venous thromboembolism, fueling a plethora of medical research and technological developments over the next century. Despite the advances made, venous thromboembolism remains an elusive entity because of its atypical presentations and associated diagnostic challenges.

This book is a fresh synthesis of venous thromboembolism care and considers the opinions and studies from different fields of medicine. As venous thrombosis spectrum is wide and can affect many organ systems, from deep veins of the leg to the cerebral venous system, our intent is for this to be a comprehensive, up-to-date and readable book. Section 1 covers the etiology of venous thrombosis and specific disease conditions that are largely associated with venous thrombosis. Section 2 is a review of the current catheter-based therapy and late complications of the venous thrombosis. Section 3 covers all aspects of assessment of the patients with cerebral venous thrombosis and venous thrombosis of the eye. Section 4 focuses on venous thrombosis in general surgery patients and catheter-related venous thrombosis in cancer patients. Section 5 covers special issues about venous thrombosis, clinical experiences and perspectives of the authors about the special topics.

We sought the best contributing authors to write these chapters. Many of them are not only experts in their assigned topics, but also have extensive teaching experience. We encouraged all contributors to present a new synthesis of the existing material infused with new ideas and perspectives, their own clinical studies and even case-reports.

So, we present to you the fruits of our efforts. We all hope that this book will be a significant contribution to the scientific knowledge about venous thrombosis.

> **Dr. Ertugrul Okuyan**  Istanbul Bagcilar Education and Research Hospital Cardiology Clinic, Istanbul Turkey

**Part 1** 

**Etiology** 

**Part 1** 

**Etiology** 

**1** 

*Kuwait* 

Mehrez M. Jadaon *Kuwait University* 

**Aetiology of Venous Thrombosis** 

Blood is a fluid tissue that circulates in the body inside intact blood vessels (veins, arteries and capillaries) to perform several vital functions. For perfect performance, blood should flow smoothly inside blood vessels without interruption. If a blood vessel gets injured or perforated, blood will flow out and be lost, which may be fatal. To prevent this, several natural physiological processes occur to form a "plug", usually called "blood clot", to block the puncture and prevent blood loss. These processes are called "Haemostasis", which involves the blood vessels themselves, specialized blood cells called platelets, as well as specific blood proteins called clotting factors. Haemostasis functions to prevent blood loss from injured blood vessels and ensure the fluidity of blood inside intact (uninjured) blood

Like any other physiological process in the body, haemostasis may get abnormal due to many reasons. It may not be able to function well and therefore the blood becomes unable to clot, which leads to bleeding problems (haemophilia). On the other hand, haemostasis may happen abnormally inside intact blood vessels, without any injury, forming a blood clot (thrombus) inside the vessel (intravascular thrombosis), which may lead to partial or complete blockage of blood flow through this vessel. This mostly occurs in the deep veins of the lower extremities, and to a less extent in the upper extremities, and this pathological condition is called deep vein thrombosis (DVT). If a thrombus detaches (called embolus), it usually goes up through the circulation and settles in an arterial branch in the lungs causing pulmonary embolism (PE). DVT and PE together are called venous thromboembolic disorders (VTE). VTE are serious vascular conditions that account for high morbidity and mortality rates in many countries with

Several "genetic" and "acquired" risk factors were identified to cause VTE, and this is why the WHO expert group described VTE in 1996 as being genetically determined, acquired or both (Lane et al., 1996). This chapter describes the different genetic and acquired risk factors for VTE. The chapter is divided into two main sections: genetic factors and acquired factors, and it is concluded by a third section on intersections of risk factors. In order to better understand how these factors cause VTE, a preliminary section is given to explain the major processes of haemostasis, namely the Coagulation and Fibrinolysis processes, and how

As explained above, haemostasis is the normal physiological process by which an injured blood vessel is sealed by a blood clot to prevent blood loss. Haemostasis involves many

vessels (Hoffbrand et al., 2001; Escobar et al., 2002; Laffan & Manning, 2002a).

an annual incidence of 1/1000 (Dahlbäck, 1995; Ridker et al., 1997).

abnormalities may lead to VTE.

**2. Coagulation and Fibrinolysis** 

**1. Introduction** 

Mehrez M. Jadaon *Kuwait University Kuwait* 

### **1. Introduction**

Blood is a fluid tissue that circulates in the body inside intact blood vessels (veins, arteries and capillaries) to perform several vital functions. For perfect performance, blood should flow smoothly inside blood vessels without interruption. If a blood vessel gets injured or perforated, blood will flow out and be lost, which may be fatal. To prevent this, several natural physiological processes occur to form a "plug", usually called "blood clot", to block the puncture and prevent blood loss. These processes are called "Haemostasis", which involves the blood vessels themselves, specialized blood cells called platelets, as well as specific blood proteins called clotting factors. Haemostasis functions to prevent blood loss from injured blood vessels and ensure the fluidity of blood inside intact (uninjured) blood vessels (Hoffbrand et al., 2001; Escobar et al., 2002; Laffan & Manning, 2002a).

Like any other physiological process in the body, haemostasis may get abnormal due to many reasons. It may not be able to function well and therefore the blood becomes unable to clot, which leads to bleeding problems (haemophilia). On the other hand, haemostasis may happen abnormally inside intact blood vessels, without any injury, forming a blood clot (thrombus) inside the vessel (intravascular thrombosis), which may lead to partial or complete blockage of blood flow through this vessel. This mostly occurs in the deep veins of the lower extremities, and to a less extent in the upper extremities, and this pathological condition is called deep vein thrombosis (DVT). If a thrombus detaches (called embolus), it usually goes up through the circulation and settles in an arterial branch in the lungs causing pulmonary embolism (PE). DVT and PE together are called venous thromboembolic disorders (VTE). VTE are serious vascular conditions that account for high morbidity and mortality rates in many countries with an annual incidence of 1/1000 (Dahlbäck, 1995; Ridker et al., 1997).

Several "genetic" and "acquired" risk factors were identified to cause VTE, and this is why the WHO expert group described VTE in 1996 as being genetically determined, acquired or both (Lane et al., 1996). This chapter describes the different genetic and acquired risk factors for VTE. The chapter is divided into two main sections: genetic factors and acquired factors, and it is concluded by a third section on intersections of risk factors. In order to better understand how these factors cause VTE, a preliminary section is given to explain the major processes of haemostasis, namely the Coagulation and Fibrinolysis processes, and how abnormalities may lead to VTE.

#### **2. Coagulation and Fibrinolysis**

As explained above, haemostasis is the normal physiological process by which an injured blood vessel is sealed by a blood clot to prevent blood loss. Haemostasis involves many

factor IX. Activated clotting factor IX, with the help of clotting co-factor VIII, is capable of activating clotting factor X in the Common pathway. So, both the Extrinsic and Intrinsic pathways team up to activate the Common pathway. In the Common pathway, activated clotting factor X, with the help of clotting co-factor V, continues the process by activating clotting factor II (prothrombin) into thrombin. The main function of thrombin is the conversion of fibrinogen (clotting factor I) into fibrin. Fibrin molecules then polymerize to form thread-like structures which form a mesh that gives the basis of blood clot. Finally, clotting factor XIII crosslinks fibrin polymers to form a stable fibrin mesh which traps activated platelets and other blood cells to form the final blood clot which eventually blocks the injured blood vessel. In addition to co-factors V and VIII, phospholipids and calcium ions (factor IV) act as co-factors in the process of Coagulation (Kane & Davie, 1988; Furie & Furie, 1988; Walker & Fay, 1992; Davie, 1995; Hoffbrand et al., 2001; Escobar et al., 2002;

After clot formation, wound healing starts and the injured blood vessel regenerates and becomes intact again. When the healing process is complete, the fibrin clot will no longer be needed and therefore it has to be removed. This occurs by the process of Fibrinolysis (figure 2). The key enzyme in this process is plasmin, which normally circulates in the blood in an inactive form called plasminogen. Plasminogen is usually activated into plasmin by tissue plasminogen activator (tPA) produced by the endothelial cells in the healing blood vessels. Plasmin breaks down fibrin threads into smaller pieces called fibrin degradation products (FDP) which are excreted from the circulation, and therefore the clot dissolves and the blood flow recovers normally (Rock & Wells, 1997; Hoffbrand et al., 2001; Escobar et al., 2002;

Fig. 2. Fibrinolysis process and its control elements. Solid arrows indicate activation; dotted

The processes of Coagulation and Fibrinolysis are carefully monitored and supervised by several control systems. This is important to prevent excessive or unnecessary coagulation or fibrinolysis. In the Coagulation process, thrombin is a very robust enzyme which exerts many coagulation functions. It can activate other clotting factors and form many positive feedback loops in the Coagulation process. Therefore, the clotting process may continue

arrows indicate inactivation (prepared and drawn by the author).

Laffan & Manning, 2002a).

Laffan & Manning, 2002a).

processes, two of which are "The Coagulation Process" and "The Fibrinolysis Process". In both processes, blood clotting factors are the crucial constituents. Clotting factors are enzymatic proteins that are synthesised mostly in the liver and circulate in the blood in an inactive form. When a blood vessel gets injured, these factors get activated and start a cascade of chemical reactions leading to the formation of a fibrin "clot" which blocks the site of injury and therefore prevents blood loss and allows for wound healing. Although the clotting factors have specific names, they are usually given Roman numerals. Figure 1 gives a schematic drawing of the process of Coagulation showing the participation of each clotting factor.

Fig. 1. The Coagulation process and its control elements. Solid arrows indicate activation; dotted arrows indicate inactivation (prepared and drawn by the author).

The Coagulation process maybe virtually divided into three pathways: Extrinsic, Intrinsic and Common pathways. When a blood vessel is injured, the components of the blood vessels start to activate the clotting factors by two methods. Firstly, the injured tissues release a membrane protein called thromboplastin (tissue factor [TF] or clotting factor III) which is capable of activating clotting factor VII in the Extrinsic pathway. Activated clotting factor VII (VIIa) forms a complex with TF, and this tends to activate clotting factor X in the Common pathway. On the other hand, the subendothelial layers of blood vessels have abundant amounts of collagen embedded inside them. This collagen gets exposed in injured vessels, and collagen is capable of activating clotting factor XII in the Intrinsic pathway. Activated factor XII (XIIa) in turn activates clotting factor XI, which in turn activates clotting

processes, two of which are "The Coagulation Process" and "The Fibrinolysis Process". In both processes, blood clotting factors are the crucial constituents. Clotting factors are enzymatic proteins that are synthesised mostly in the liver and circulate in the blood in an inactive form. When a blood vessel gets injured, these factors get activated and start a cascade of chemical reactions leading to the formation of a fibrin "clot" which blocks the site of injury and therefore prevents blood loss and allows for wound healing. Although the clotting factors have specific names, they are usually given Roman numerals. Figure 1 gives a schematic drawing of the process of Coagulation showing the participation of each clotting

Fig. 1. The Coagulation process and its control elements. Solid arrows indicate activation;

The Coagulation process maybe virtually divided into three pathways: Extrinsic, Intrinsic and Common pathways. When a blood vessel is injured, the components of the blood vessels start to activate the clotting factors by two methods. Firstly, the injured tissues release a membrane protein called thromboplastin (tissue factor [TF] or clotting factor III) which is capable of activating clotting factor VII in the Extrinsic pathway. Activated clotting factor VII (VIIa) forms a complex with TF, and this tends to activate clotting factor X in the Common pathway. On the other hand, the subendothelial layers of blood vessels have abundant amounts of collagen embedded inside them. This collagen gets exposed in injured vessels, and collagen is capable of activating clotting factor XII in the Intrinsic pathway. Activated factor XII (XIIa) in turn activates clotting factor XI, which in turn activates clotting

dotted arrows indicate inactivation (prepared and drawn by the author).

factor.

factor IX. Activated clotting factor IX, with the help of clotting co-factor VIII, is capable of activating clotting factor X in the Common pathway. So, both the Extrinsic and Intrinsic pathways team up to activate the Common pathway. In the Common pathway, activated clotting factor X, with the help of clotting co-factor V, continues the process by activating clotting factor II (prothrombin) into thrombin. The main function of thrombin is the conversion of fibrinogen (clotting factor I) into fibrin. Fibrin molecules then polymerize to form thread-like structures which form a mesh that gives the basis of blood clot. Finally, clotting factor XIII crosslinks fibrin polymers to form a stable fibrin mesh which traps activated platelets and other blood cells to form the final blood clot which eventually blocks the injured blood vessel. In addition to co-factors V and VIII, phospholipids and calcium ions (factor IV) act as co-factors in the process of Coagulation (Kane & Davie, 1988; Furie & Furie, 1988; Walker & Fay, 1992; Davie, 1995; Hoffbrand et al., 2001; Escobar et al., 2002; Laffan & Manning, 2002a).

After clot formation, wound healing starts and the injured blood vessel regenerates and becomes intact again. When the healing process is complete, the fibrin clot will no longer be needed and therefore it has to be removed. This occurs by the process of Fibrinolysis (figure 2). The key enzyme in this process is plasmin, which normally circulates in the blood in an inactive form called plasminogen. Plasminogen is usually activated into plasmin by tissue plasminogen activator (tPA) produced by the endothelial cells in the healing blood vessels. Plasmin breaks down fibrin threads into smaller pieces called fibrin degradation products (FDP) which are excreted from the circulation, and therefore the clot dissolves and the blood flow recovers normally (Rock & Wells, 1997; Hoffbrand et al., 2001; Escobar et al., 2002; Laffan & Manning, 2002a).

Fig. 2. Fibrinolysis process and its control elements. Solid arrows indicate activation; dotted arrows indicate inactivation (prepared and drawn by the author).

The processes of Coagulation and Fibrinolysis are carefully monitored and supervised by several control systems. This is important to prevent excessive or unnecessary coagulation or fibrinolysis. In the Coagulation process, thrombin is a very robust enzyme which exerts many coagulation functions. It can activate other clotting factors and form many positive feedback loops in the Coagulation process. Therefore, the clotting process may continue

Fig. 3. Balance between the Coagulation and Fibrinolysis processes, in health and disease

production of these proteins and therefore lower control over the Coagulation process. This usually leads to an increase in the rate of coagulation, a phenomenon called "hypercoagulability", which is usually manifested clinically in patients as VTE. On the other hand, the natural anticoagulants may be produced normally, but they can not exert their function normally on their targets, and therefore hypercoagulability and VTE are expected too. Also, certain genetic defect may affect the clotting factors themselves leading to overproduction of such factors causing hypercoagulability. Moreover, abnormalities in the Fibrinolysis process may lower the efficiency of removal of clot, which leads to accumulation of clots and formation of thrombosis. In the following lines, several genetic abnormalities (risk factors) leading to venous thrombosis are discussed. These usually cause VTE at relatively earlier ages (less than 40 years-old) and may be referred to as "familial or hereditary thrombophilia". Although the condition known as "Activated Protein C Resistance" is the most common genetic defect associated with VTE, this defect will be left till the end because it was discovered relatively more recently and it was found to be the

Historically, Egeberg (1965) was the first to associate cases of venous thrombosis with a hereditary defect in the Coagulation system; namely AT deficiency. AT is an inhibitor for thrombin, and its inhibition action is largely enhanced by heparin as a co-factor. AT deficiency causes lower control over thrombin, and therefore the Coagulation process becomes overactive (hypercoagulability) leading to VTE. Also, decreased control over

(prepared and drawn by the author).

**3.1 Antithrombin (AT) deficiency** 

most common and important genetic risk factor for VTE.

forever and the clot may enlarge until it blocks the whole lumen of the blood vessel. Therefore, the Coagulation process should be limited to the area of blood vessel injury and should be prevented from extending abroad. This is achieved by three main proteins that circulate normally in the blood, namely protein C (PC), protein S (PS) and antithrombin (AT). Together they are called "natural anticoagulants" since they function as antagonists to clotting. They exert their function after a blood clot is formed to prevent excessive clotting. They also interfere with the Coagulation process if it starts working accidently inside intact blood vessels. To explain more, AT, as its name indicates, inactivates thrombin, and therefore stops the process of Coagulation. PC, which is first activated into activated protein C (APC), tends to breakdown co-factors V and VIII and therefore slows down the Coagulation process. For APC to function normally, PS is involved as a cofactor. Phospholipids and calcium ions also assist in this process. Another inhibitor specific for the Extrinsic pathway, namely Tissue Factor Pathway Inhibitor (TFPI), limits the action of TF in activating factor VII (Kalafatis et al., 1994; Novotny, 1994; Davie, 1995; Esmon et al., 1997; Rosing & Tans, 1997; Cella et al., 1997; Hoffbrand et al., 2001; Escobar et al., 2002; Laffan & Manning, 2002a).

Regarding the control of the Fibrinolysis process, there are many proteins involved. For example, plasminogen activator inhibitors (PAI) prevent tPA from activating plasminogen and therefore stop the initiation of fibrinolysis. This is important to avoid early removal of blood clot before the completion of blood vessel healing. Another anti-fibrinolysis protein is α2-antiplasmin (AP) which is a major inhibitor of plasmin. Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) is a protein that is activated by thrombin to prevent the binding of plasmin to fibrin and therefore stops plasmin from breaking down the clot. The control actions of these fibrinolysis antagonists are illustrated in figure 2 (Hoffbrand et al., 2001; Escobar et al., 2002; Laffan & Manning, 2002a).

For normal healthy clotting/anticlotting results, the Coagulation and Fibrinolysis processes, with their control systems, should work in a highly balanced manner. Any abnormalities may disturb this balance leading to serious consequences. Abnormalities can be quantitative (deficiency or increase in quantity) or qualitative (abnormal structure or function [loss, lowering or gain]) that may affect any of the proteins involved. For example, abnormalities in clotting factors may lead to bleeding problems (termed haemophilia), while abnormalities in the natural anticoagulants may lead to increased clotting tendency (termed hypercoagulability) leading to thrombosis, with certain exceptions in both (figure 3).

In the following sections, different genetic and acquired abnormalities affecting the Coagulation and Fibrinolysis processes are discussed. Only those leading to thrombosis are included in accordance with the scope of this chapter. These abnormalities are usually referred to as "risk factors" since they put forth clinical manifestations in patients suffering from these abnormalities.
