1048 lACC Vol x, No 6 December IQX6 Ill4B-IIJB VENOUS THROMBOEl\1BOLISM Epidemiology and Pathogenesis of Venous Thrombosis JACK HIRSH, MD, FRACP, FRCP(C), FACP,* RUSSELL D. HULL, MBBS, MSc, FRACP, FRCP(C), FACP, FCCP,t GARY E. RASKOB, BSc (HaNS), MSc* Hamilton. Ontario. Canada Venous thrombi are intravascular deposits composed otherwise healthy individuals. Screening studies with predominantly of fibrin and red blood cells with a vari• iodine-l25 fibrinogen leg scanning, impedance plethys• able platelet and leukocyte component. They frequently mography and perfusion lung scanning have shown that arise in large venous sinuses in the calf, in valve cusp the majority of venous thrombi and pulmonary emboli pockets either in the deep veins of the calf or thigh or that occur in hospitalized patients are small and asymp• in venous segments that have been exposed to direct tomatic, and it is likely that most are clinically insignif• trauma. Venous thrombosis can be produced experi• icant. In bedridden patients, most thrombi commence mentally by a combination of stasis and systemic hy• in the calf and are asymptomatic. When a calf vein percoagulability or by stasis and endothelial damage. thrombus extends into the proximal venous segment, the Thrombosis is augmented if the fibrinolytic mechanism risk of clinically significant pulmonary embolism in• is inhibited or defective. A number of clinical conditions creases. Less is known about the incidence and clinical and laboratory abnormalities are associated with and significance in a nonhospital population; although predipose to venous thrombosis and, in many of these, asymptomatic disease occurs, its frequency is unknown. it is possible to identify one or more of the thrombogenic In contrast to the patients with asymptomatic venous factors discussed. thrombosis, symptomatic patients with venous throm• Venous thromboembolism (venous thrombosis and bosis usually have large occulsive thrombi localized in pulmonary embolism) is a serious and potentially fatal their proximal veins. disorder that usually complicates the course of sick hos• (J Am Coli CardioI1986;8:104B-113B) pitalized patients, but occasionally affects ambulant and Epidemiology patients, but it is clear from recent studies (1-4) that venous Venous thrombosis can involve the superficial leg veins, thromboembolism also affects ambulant and otherwise healthy deep veins of the calf (calf vein thrombosis) and deep veins individuals. Over the last decade, screening studies (5) with above the knee (popliteal and more proximal veins [proximal iodine-l 25 fibrinogen leg scanning have shown that venous vein thrombosis]). Thrombosis of the superficial veins of the thrombosis is common in hospitalized patients, but that more legs frequently occurs in varicosities and is usually benign than 80% of the thrombi detected are small, asymptomatic, and self-limiting. Thrombosis of the deep calf vein is a less confined to the calf and probably clinically insignificant. serious disorder than proximal vein thrombosis because the Autopsy studies (6) have also demonstrated a high frequency thrombi are generally smaller in patients with calf vein of pulmonary embolism, which although the majority are thrombosis and are less frequently associated with clinical small and clinically insignificant, the fact remains that fatal disability or major complications. pulmonary embolism is one of the most common prevent• Incidence. Deep venous thrombosis and pulmonary em• able causes of hospital death. Fatal pulmonary embolism bolism usually complicate the course of sick hospitalized has been reported (7,8) in 4 to 7% of patients after emer• gency hip surgery, in 0.3 to 1.7% of patients after elective hip replacement and 0.1 to 0.8% ofgeneral surgical patients. From the Departments of Medlcine* and Clinical Epidemiology and The frequency and distribution of venous thromboem• Biostatistics,t McMaster University, Chedoke-McMaster Hospitals, Ham• bolism in ambulatory patients has been much more difficult ilton, Ontano. Canada. to study. However, as mentioned, recent experience since Address for reprints: Jack HlfSh, MD, Department of Medicine, Room 3WIO, McMaster University, 1200 Main Street West, Hamilton, Ontario, the provision of a noninvasive diagnostic service indicates Canada L8N 325. that venous thrombosis is not uncommon in ambulant non- © 1986 by Ihe AmerIcan College of CardIOlogy 0735-1097/86/$350 lACC Vol 8. No 6 HIRSH ET AL 105B December 1986.1 04B~ 113B VENOUS THROMBOSIS hospitalized patients. When patients with venous thrombosis Pathogenesis of Venous Thromboembolism develop symptoms, they usually have large occlusive thrombi, Venous thrombi are composed predominantly of fibrin 'and approximately 80% of these are either located or extend and red blood cells with a variable platelet and leukocyte into the popliteal or more proximal veins at the time of component (17). They frequently arise in large venous si• presentation (3,9). Symptomatic pulmonary embolism oc• nuses in the calf, in valve cusp pockets either in the deep curs in ambulant patients (3) more frequently than is gen• veins of the calf or thigh (18,19) or in venous segments that erally appreciated, but fatal pulmonary embolism is uncom• have been exposed to direct trauma (20,21). mon. Experimental venous thrombosis can be produced by a Fate of venous thrombosis. When symptoms or signs combination of stasis and an increase in blood coagulability of venous thrombosis occur, they are caused either by ob• or by a combination of stasis and endothelial damage (22,23). struction to venous outflow, inflammation of vessel wall or Predisposing factors. Clinically, the major predispos• perivascular tissue, a combination of these two factors or ing factors to venous thrombosis are activation of blood embolization of the thrombus into the pulmonary circula• coagulation, venous stasis and vascular wall damage tion. The fate of a venous thrombus is determined by the (21,22,24). These three factors are interrelated and, thus, balance between factors that either promote further depo• venous thrombosis may occur when blood coagulation is sition of fibrin onto the thrombus or that lead to its removal. activated by the release of tissue thromboplastin from in• Extension of thrombosis is more likely to occur if the orig• jured or infarcted tissue (25-27) or when blood coagulation inal thrombogenic stimulus persists (for example, tissue in• is activated locally by vessel wall damage (20,24). The jury, stasis or vascular damage) or if marked endothelial thrombogenic effect of activation of blood coagulation is damage or stasis occurs as a consequence of the original augmented by venous stasis and reduced by rapid blood acute venous thrombosis. The factors that lead to the re• flow. For example, as discussed later, one of the reasons moval of thrombi are fibrinolysis, digestion of fibrin by is that venous stasis impairs the clearance of activated co• leukocytes, organization of the thrombus and embolization. agulation factors by the liver and results in an increase in Complete spontaneous lysis of large venous thrombi is un• the concentration of activated coagulation factors through common and, even when patients with venous thrombosis the autocatalytic activity of the coagulation system (22,28). are treated with heparin, complete lysis occurs in less than Thrombogenesis. Thrombogenesis is modulated by in• 10% of cases (10,11). In contrast, complete dissolution of activation of activated coagulation factors by circulating small, asymptomatic calf vein thrombi (detected by iodine• inhibitors (29-32), the dissolution and clearance ofactivated 125 fibrinogen leg scanning) occurs quite frequently (5). coagulation factors by flowing blood, the removal of acti• Pulmonary embolism is commonly associated with ve• vated coagulation factors by the liver (33), the clearance of nous thrombosis. Clinically silent pulmonary embolism (de• soluble fibrin complexes by reticuloendothelial cells (34) tected by perfusion lung scanning) occurs at the time of and the dissolution of fibrin by the fibinolytic system (35). presentation in about 50% of patients with documented vein thrombosis (12,13). Pulmonary emboli occur more fre• quently and are larger in patients with proximal vein throm• Thrombogenic Factors bosis than in patients with calf vein thrombosis (3). Asymptomatic venous thrombosis is also found in ap• Activation ofBlood Coagulation proximately 70% of patients who present with confirmed The coagulation proteins circulate as proenzymes that are clinically symptomatic pulmonary embolism (3) and is usu• sequentially converted to active enzymes, all of which are ally extensive, involving the proximal veins. Ifthe thrombus serine proteases (28). The blood coagulation process can be that embolizes is small (which is frequently the case when activated by the intrinsic or extrinsic pathway (36), and this it is present in the calf), the embolus is usually asymptomatic has been reviewed in the first section of this symposium. and clinically insignificant (12). However, if it is large and In brief, intrinsic pathway activation occurs when blood involves the proximal veins, it may produce clinical man• comes in contact with a foreign surface (37). Factor XII ifestations (3) and, if it is very large or if the patient has a interacts with the surface and is converted into its active compromised cardiorespiratory system, it may be fatal. Most form-factor XIIa. This, in tum, converts the zymogen clinically significant and fatal emboli