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 arise from thrombi in factor XI into factor XIa, a reaction that is calcium• the proximal veins of the leg (2). independent; all subsequent reactions except the conversion Venous thrombi usually slowly organize and recanalize of fibrinogen to fibrin require calcium. Factor XIa, in tum, and may predispose patients to the postphlebitic syndrome activates factors IX and IXa in the presence of factor VIII, because of associated venous valve damage (14). In addi• and phospholipid activates factor X. The rate of this reaction tion, patients with one episode of venous thrombosis are is greatly increased by the presence of phospholipid and by predisposed to further episodes when exposed to high risk prior exposure of factor VIII to either thrombin or factor situations (15,16). Xa (38,39). 106B HIRSH ET AL lACC Vol X. No 6 VENOUS THROMBOSIS December 1986 104B-113B

The extrinsic pathway is activated in vitro by exposing contain a cysteine protease (54), and this may be one of the blood to phospholipoprotein extracts from various tissues mechanisms by which thrombosis is induced in patients with (such as brain or lung), which are known as thromboplastins. malignant disease. Tissue thromboplastin combines with and activates factor A number of clinical risk factors could induce venous VII and the resulting factor VII complex, in tum, activates thromboembolism by activating blood coagulation (21). These factor X, thus bypassing a number of time-consuming steps include extensive surgery (55), trauma (56), bums (56), in the intrinsic clotting pathway (40,41). infusion of factors II, VII and IX and X complex (for the The intrinsic and extrinsic pathways meet at a common treatment of bleeding associated with factor IX deficiency point at the activation of factor X; beyond this point, blood or liver disease) which contain activated clotting factors, coagulation continues along a common pathway. Activated (57) disseminated malignant disease (54,57) and myocardial factor X in the presence of calcium, phospholipid and factor infarction (26). V converts prothrombin to thrombin. This reaction is also markedly accelerated by prior exposure offactor V to throm• bin. Thrombin interacts with fibrinogen and converts it into Venous Stasis fibrin monomer and fibrinopeptides A and B. The fibrin Stasis predisposes to venous thrombosis by preventing monomer fragments polymerize to form fibrin polymers, activated coagulation factors from being diluted by non• which precipitate as insoluble fibrin when a critical con• activated blood, preventing clearance of activated coagu• centration of fibrin monomer is reached (42). The fibrin lation factors, and preventing mixing of activated coagu• polymers are initially linked by noncovalent bonds, but be• lation factors with their inhibitors (21,22). come covalently bound under the influence of activated fac• Physiologically, venous return from the legs is enhanced tor XIII (43). by contraction of calf muscles, which propels blood from Interactions between intrinsic and extrinsic path• the calf in the direction of the heart (59-61). Venous stasis ways. Blood coagulation is modified by a number of pos• is produced by immobility, venous obstruction, raised ve• itive and negative feedback loops and by interaction between nous pressure, increased blood viscosity and venous dila• the intrinsic and extrinsic pathways. For example, thrombin tion. and factor Xa, formed either by activation of the extrinsic Immobility. This predisposes to venous stasis and, or intrinsic pathway, feed back to activate factors VIII and therefore, thrombosis because it promotes blood pooling in V and markedly accelerate the rate of reactions involving the intramuscular sinuses of the calf (18,59,61), which are these two cofactors (36,39,44). Factor Xa feeds back to dilated with blood during recumbency (15,19). Thus, the initially increase and then inhibit its activation by factor VII prevalence of venous thrombosis found at autopsy increases (41,45). The intrinsic and extrinsic pathways are linked in steeply in patients who are confined to bed for more than a number of ways. Factor VII is activated by factor XIIa 1 week before death (59). Preoperative immobility is also (46), and factor VIla can activate factor IX directly (44,45,47). associated with a higher frequency of preoperative venous There is also evidence that the activation of factor XI can thrombosis (62,63). Postoperative patients remain at risk occur independently of factor XII through a platelet-related during the entire period of immobility, and late postoper• reaction (48). ative thrombosis is not prevented in patients who have pro• Mechanisms for activation of venous blood coagula• phylaxis in the first postoperative week (either with low tion. The precise mechanism or mechanisms for activation dose heparin or with intermittent pneumatic compression) of blood coagulation, particularly for the venous system, is if they remain immobile beyond the period of prophylaxis uncertain. There are a number of theoretic possibilities. (64,65). Immobility contributes to the higher incidence of Activation of the intrinsic pathway may occur by contact postoperative venous thrombosis in patients who undergo of factor XII with collagen on the exposed subendothelium hysterectomy or prostectomy using the abdominal route than of damaged vessels (49,50). Coagulation may be further in those who have vaginal hysterectomy and transurethral augmented through a platelet-related mechanism because prostatectomy (15,66-70). Immobility also contributes to platelets that have been exposed to collagen or adenosine the high frequency of thrombosis after hip surgery (20, diphosphate (ADP) accelerate the activation of factors XII 70-73) and knee surgery (74,75) and in patients who have and XI (48). The extrinsic pathway may be activated by the fractures of the lower limb. release of tissue thromboplastin into the bloodstream during The effect of immobility on thrombosis is well illustrated cell damage (25,27) and by the exposure of blood to tissue by comparing the location of thrombosis in stroke patients thromboplastin, which is made available locally as a result (76,77) with that in paraplegic patients (78). Venous throm• of vascular wall damage (51) and by activated leukocytes bosis is a common complication in both groups, but the that migrate to areas of vascular damage (52,53). Factor X frequency of thrombosis is four to nine times greater in the can be activated directly by extracts of malignant cells that paralyzed than in the nonaffected limb in patients with stroke; JACC Vol 8. No 6 HIRSH ET AL 107B December 1986 104B-1 13 B VENOUS THROMBOSIS

it occurs with equal frequency in both legs in paraplegic Circulating Inhibitors patients (76,78). Immobility also contributes to the high prevalence of thrombus in patients with cardiac failure and Three plasma proteins have been identified as important other serious medical illnesses. modulators of activation of blood coagulation. These are Venous obstruction. This may occur as a result ofeither antithrombin III, protein C and protein S. extrinsic compression or intraluminal obstruction secondary Antithrombin III. This is an important coagulation in• to a previous venous thrombosis. Stasis produced by venous hibitor (30,31,88). It inhibits activated factors XII, XI, IX, obstruction probably contributes to the risk ofvenous throm• X and thrombin (although inhibition of factors XIIa and XIa bosis in patients with pelvic tumor and to recurrent venous is relatively minor), and the rate of its inhibition of these thrombosis in patients with persistent obstruction due to enzymes is markedly increased by heparin (30,31). proximal vein thrombosis (79). Reduction of antithrombin III levels to approximately Elevated venous pressure. This produces venous stasis 50% of normal predisposes to venous thrombosis (89-94). and predisposes to the high prevalence of venous thrombosis Although antithrombin III is a relatively slow inactivator of in patients with heart failure (80,81). these activated clotting factors in the absence of heparin, a Blood viscosity. Blood flow and blood viscosity are heparin-like glycosaminoglycan has been reported (95,96) closely linked (82). Blood viscosity increases in regions of on the luminal surface of endothelial cells, so that a 50% slow flow. However, blood viscosity is increased in poly• reduction in antithrombin III might seriously limit the neu• cythemia vera and erythrocytosis (because of hypergam• tralization of activated coagulation factors on endothelial maglobulinemia) and in some postoperative patients and surface. inflammatory states (because of an increase in fibrinogen Thrombin binds to receptors on the endothelial cell sur• concentration) (83,84). It is possible that the increased prev• face, where it is inactivated by circulating antithrombin III. alence of venous thrombosis in these conditions is caused One of these receptors is thrombomodulin, and others may by stasis induced by an increase in blood viscosity. be glycosaminoglycan bound to endothelium. Thrombin bound Venous dilation. This occurs in patients with varicose to endothelium is rapidly inactivated in the presence of veins and in elderly patients (particularly if they are bed• plasma, but only slowly if the plasma is replaced by either ridden), during pregnancy (85) and in individuals taking antithrombin III or antithrombin III-depleted plasma. Thus, estrogen-containing oral contraceptive pills (85). Stasis due potentiation of the inhibition of endothelial cell-bound to venous dilation could contribute to the increased risk of thrombin by glycosaminoglycan appears to be dependent on thrombosis in these patient groups. the presence not only of antithrombin III, but also of an additional plasma factor. Vessel Wall Damage There have been a number of reports (89-94) of idio• pathic and secondary venous thrombosis occurring in fam• As discussed, damage to the venous endothelium results ilies with a deficiency of antithrombin III. The trait is in• in the exposure of blood to subendothelium, which in tum herited in an autosomal dominant manner, and affected patients leads to platelet adhesion and aggregation (23,86), local have antithrombin III levels of 40 to 60% of normal. Al• accumulation of leukocytes (53), activation of the intrinsic though it is difficult to obtain exact figures on the risk of pathway through activation of factor XII by collagen (49) thrombosis in affected individuals because of the likelihood and activation of factors XII and XI by activated platelets of a reporting bias, review of the literature indicates that (48). Activation of the extrinsic pathway also occurs by more than 50% of affected individuals develop thromboem• tissue thromboplastin derived from the damaged vessel wall bolic events before the age of 50 years. Thrombosis usually (51) and activated leukocytes (87). occurs in the deep veins of the legs or as a pulmonary Venous damage is probably the main contributor to ve• embolism, but there are reports (84) ofthrombosis occurring nous thrombosis in patients undergoing hip surgery (20), in usual sites such as the mesenteric veins. knee surgery and varicose vein stripping in patients with Decreased antithrombin III levels also occur in liver severe bums and lower limb trauma (56). disease and during heparin therapy. In patients with liver disease, this decrease may contribute to the increased risk of thrombosis that has been reported (97) in these patients Protective Mechanisms after infusions of concentrates containing factors II, VII, These mechanisms will be described in more detail than IX and X. There is no evidence that the mild reduction in in previous sections since their preventive role in venous antithrombin III that occurs during heparin therapy is clin• thromboembolic disease is better known. On the other hand, ically important. a decrease or absence ofone of these protective mechanisms Protein C. This is a zymogen whose synthesis is vitamin may predispose to venous thrombosis. K-dependent (98). Like other vitamin K-dependent coag- 1088 HIRSH ET AL lAce Vol X. No 6 VENOUS THROMBOSIS Decemher 19X6 1ll4B-113B

ulation factors. protein C contains a number of gamma• quately cleared in patients with liver disease and, thus, lead carboxyglutamic acid residues (99). The amino acid se• to thrombosis (57,116,117). quence of bovine protein C has recently been determined (100). Protein C is activated by thrombin (29). The activation Fibrinolytic System process is greatly enhanced by interaction of thrombin with The basic reaction of the plasma fibrinolytic system is the endothelial cell surface factor thrombomodulin (10 I). the conversion of beta-globulin plasminogen to plasmin by Activated protein C is a potent anticoagulant (102) that proteolytic cleavage mediated by a number of plasminogen inactivates activated factors V and VIII and also stimulates activators (35,118). At least two plasminogen activators. fibrinolysis (32.103). Walker (104) reported that another tissue plasminogen activator and urokinase. are synthesized vitamin K-dependent protein (protein S) is a cofactor for by and released from endothelial cells. Plasmin has the activated protein C. (104). capacity to hydrolyze fibrin (the desired physiologic sub• Deficiency ofprotein C is associated with familial venous strate) and various plasma coagulation proteins including thrombosis (105-107). Protein C deficiency is also inherited fibrinogen and factors VII and V (35). Like the coagulation in an autosomal dominant manner. The level of protein C system, the activity of the fibrinolytic system is modulated in affected members is 40 to 60% of normal. similar to that by inhibitors that inhibit both the activation of plasminogen seen in patients with antithrombin III deficiency. Most pa• and the proteolytic effect of plasmin (35,119). tients have venous thromboembolism. Mesenteric vein Decreased fibrinolytic activity. This has been reported thrombosis has also been described, and there have been in patients in the early postoperative period (120-124), in isolated reports of stroke and myocardial infarction occur• individuals taking oral contraceptives (125), during the last ring at a relatively early age. However, there is no con• trimester of pregnancy (126-128) and in obese individuals vincing evidence that protein C predisposes to arterial (62,128,130). Fibrinolytic activity has been found to be less thrombosis. in leg veins than in arm veins (131, 132), an observation Protein S. This is a vitamin K-dependent plasma protein that may explain, in part. the greater tendency for venous that is a cofactor for activated protein C and is required for thrombosis to occur in leg veins. The relative deficiency of the expression of the anticoagulant effect of protein C fibrinolytic activity in leg veins appears to be more marked (108-110). Despite its relatively recent discovery, protein in the elderly (132), which may explain, in part, the im• S deficiency has already been reported (108.111-114) in portance of old age as a risk factor in thrombosis. An as• more than 50 patients with recurrent venous thrombosis. sociation between defective fibrinolysis and postoperative Venous thromboembolism is often idiopathic, may be fa• thrombosis has been observed when fibrinolytic activity is milial and frequently occurs before the age of 30 years. The measured preoperatively and on the first postoperative day clinical disorder affects both sexes equally, and is expressed (120-124). Postoperative venous thrombosis has been re• in heterozygotes whose levels of functional protein S are in ported to occur more frequently in patients who have re• the range of 15 to 50% of normal (108.11 I). Preliminary duced fibrinolytic activity detected either as a high anti• reports suggest that patients can be treated effectively with plasmin level or as reduced plasminogen activator level long-term oral anticoagulant therapy. (120-124). Heparin cofactor II. This is a plasma protein that in• Relation between reduced fibrinolytic activity and re• hibits thrombin activity by forming a covalent complex with current venous thromboembolism. There have been a the enzyme. The formation of the complex is catalyzed by number of reports (132-135) that patients with recurrent heparin and dermatan sulfate. There have been two reports superficial and deep vein thrombosis have reduced fibri• of thrombosis associated with heparin cofactor deficiency, nolytic activity measured either as vessel wall plasminogen but a definite causal relation has not been established (115). activator (from biopsy specimens of superficial veins) or as circulating plasminogen activator. In uncontrolled studies (133,136). treatment of some of these patients with anabolic steroids has been reported to both increase fibrinolytic ac• tivity and reduce the frequency of recurrent venous throm• Hepatic Inactivation ofActivated bosis (136,137). Coagulation Factors Recurrent venous thrombosis and pulmonary embolism The liver removes activated coagulation factors from blood has been reported in a patient who had decreased levels of (33). Thrombosis has been reported in patients with liver plasminogen when measured immunologically (138). Other disease after the infusion of concentrates of factors II, VII, members of the patient's family also had a reduced ratio of IX and X (57). These concentrates contain a small amount functional to immunologic plasminogen, but did not have of activated coagulation factors, which may not be ade- a history of thrombosis. Further evidence for a relation JACC Vol ~,No 6 HIRSH ET AL 109B December 1986 I04B-113B VENOUS THROMBOSIS

between reduced fibrinolytic activity and thrombosis comes have less releasable activator in endothelial cells, Other from a report (138) of high antiplasmin levels occurring in unknown mechanisms also probably contribute to the very a family with idiopathic pulmonary hypertension. high risk of venous thrombosis that occurs with advanced age, Malignancy. Patients with malignant disease may de• Clinical Risk Factors and Their Relation velop recurrent superficial deep vein thrombosis, thrombosis in unusual sites and, rarely, thrombosis that is resistant to to Thrombogenesis anticoagulant therapy, The frequency of postoperative ve• Surgery and trauma. A number of well recognized nous thrombosis increases two- to threefold in patients thrombogenic factors are associated with surgery and trauma. undergoing surgery for malignant disease when compared These include I) increased blood coagulability due to release with similar surgical procedures for nonmalignant condi• of tissue thromboplastin into the blood (25,27); 2) stasis tions (15,55,62). However, the extent of surgery could be due to immobilization preoperatively, during operation and greater in patients with malignant disease, so that the effect during the postoperative period and in patients with a plaster of malignancy as an independent risk factor for thrombosis cast (59-63); and 3) reduced fibrinolytic activity, which is difficult to determine in these postoperative patients (142). occurs in many patients within 24 hours of surgery A number of factors could contribute to the increased (119,123,124). In addition, surgery or trauma to the lower risk ofvenous thrombosis in patients with malignant disease. limb may produce local vessel damage (20). Material that has both tissue thromboplastin-like activity and The risk of thromboembolism after surgery is related to factor X-activating activity has been isolated from malignant the site and extent of surgical trauma as well as to duration tissues (54,58), and patients with cancer have been reported and nature of the operative procedure and the length of time to have reduced fibrinolytic activity (143), Malignant tumors that the patient remains immobilized preoperatively and may either compress or infiltrate veins and so predispose to postoperatively (15,62,140). Orthopedic surgical proce• thrombosis. Patients with malignant disease have associated dures of the lower limb and trauma to the pelvis and lower confounding risk factors in that they tend to be older and, limb carry a particularly high risk, Approximately 20% of as mentioned, require more extensive and prolonged surgery thrombi in patients who have hip surgery are localized to than those with benign disease. the femoral vein close to the site of surgery (20,71,141). Heart failure. Heart failure is a well recognized risk Operative venography has demonstrated that the femoral factor for venous thromboembolism, and pulmonary em• vein is markedly twisted and distorted during total hip re• bolism is an important cause of death in patients with heart placement; it is likely that endothelial damage occurs as a failure (21,81), The increased risk of venous thrombosis in consequence of this manipulation and is responsible for the these patients is contributed to by increased central venous unique localization of thrombi in the proximal venous seg• pressure and mobility, both of which lead to venous stasis. ment (20). It is of interest that more than 90% of femoral Previous venous thromboembolism. Patients with a vein thrombi occur on the side of operation, although calf history of previous venous thrombosis have a three- to four• vein thrombi tend to be evenly distributed in both legs fold increased risk of developing venous thrombosis after (20,71,141), Patients having major knee surgery or who elective abdominal surgery than do patients without such a have sustained tibial fractures requiring cast immoblization history (15,62). In addition, the rate of recurrent venous are also at very high risk of venous thrombosis (55). thrombosis is three- to fourfold greater when anticoagulant Examples of the important role of surgical trauma and therapy is discontinued after 3 months in patients with re• immobilization in the risk of thrombosis are provided by current venous thrombosis than in patients who have only comparing the thrombosis rate for abdominal hysterectomy one episode of venous thrombosis (79). The increased risk with that for vaginal hysterectomy (69) and by comparing of thrombosis in patients who have had an episode of venous suprapubic prostatectomy with transurethral prostatectomy thrombosis may be caused by venous stasis, which occurs (65-67). The risk of thrombosis is much higher when these as a consequence of valve damage, or by venous obstruction procedures are performed by an abdominal approach. or alterations in the blood (either recognized, for example, Age. Age is a very important risk factor for venous deficiency of antithrombin III, protein C, protein S, plas• thrombosis, but the underlying mechanism is uncertain minogen or possibly heparin cofactor II, or unrecognized), (15,62). Venous dilation occurs in the elderly, particularly which predisposed the patient to the initial episode. when they are confined to bed, and in addition to their Obesity. A number of studies (15,62) have reported that greatly reduced mobility, results in venous stasis, The fi• obesity is associated with an increased risk of postoperative brinolytic response to venous occlusion of the legs is re• thrombosis, Obesity has been reported to be associated with ported to be significantly lower in persons older than 65 impaired fibrinolytic activity; in addition, obese patients years of age than in those younger (132), These older people (129,130) are more likely to remain immobile for longer I lOB HIRSH ET AL lACC Vol ~. No 6 VENOUS THROMBOSIS December I Y~6 104B-113B

periods of time after operation than are their nonobese coun• References terparts. I. Coon WW. Willis PW. Keller 18 ThromboembolIsm and uther Pregnancy and the pill. Pregnancy and the estrogen• venous disease in the Tecumseh CommunIty Health Study. Circu• containing oral contraceptive pills are recognized as risk lation 1973,48:839-49. factors for venous thrombosis. However, evidence sup• 2. Hume M. Sevltt S. Thomas DP. Venous ThrombOSIS and Pulmonary Embolism. Cambndge: Harvard University Press, 1970: I. porting pregnancy as a risk factor is imperfect, and there is 3. Hull RD, Hirsh J, Carter CJ. et al. Pulmonary angiography. venti• no good evidence that the "low dose" estrogen-containing latIOn lung scanning and venography for clinically suspected pul• pill is a risk factor for venous thrombosis. monary embolism with abnormal perfUSIOn lung scan. Ann Intern A number ofthrombogenicfactors operate during normal Med 1983;98:891-9. pregnancy and delivery. These include a decrease in fibri• 4. Hull R. Hush 1. Carter C. et al. Diagnoslic efficacy of Impedance plethysmography for clInIcally suspected deep-vein thrombOSIS: a nolytic activity, which occurs in the third trimester (1 26-128) randomized trial. Ann Intern Med 1985;102:21-6. and in the early stages of labor before placental separation 5. Kakkar VV. Flank C. Howe CT, et al. Natural history of postop• (127), release of tissue thromboplastin into the circulation erative deep vein thrombosu,. Lancet 1969;li:230-3. at the time of placental separation (126), venous stasis, 6. Morrell MP. Dunhill MS. The postmortem inCidence of pulmonary which occurs as a result of deep venous dilation (85), and embolism in a hospital populatIOn. Br J Surg 1968;55'347-52. pressure of the uterus during the third trimester ofpregnancy 7. Gallus AS, Hirsh J. Prevenlion of venous thromboembolism. Semin and during delivery. There is also an increased level of Thromb Hemost 1976;2:232-90. plasma fibrinogen and coagulation factors VII, VIII and IX 8. Hirsh J, Genton E. Hull RD. A practical approach to the prophylaxis of venom, thrombosis In: Hirsh J. Genton E. Hull R. eds. Venous during pregnancy, but these are unlikely to contribute to the Thromboembolism. New York: Grune & Stratton. 1981:108-21. risk of thrombosis (126). Estrogens in oral contraceptive 9. Hull RD. Hirsh J, Sackett DL, et al. Replacement of venography in pills produce many of the changes that occur in pregnancy. suspected venous thrombOSIS by impedance plethysmography and They produce venous dilation (85) and, in some studies, !>51-fibrinogen leg scanning. Ann Intern Med 1981;94:12-5. estrogens have been reported to decrease functional levels 10. Gallus AS, Hirsh J Treatment of venous thromboembolic disease. Semin Thromb Hemost 1976;2:291-331. of antithrombin III (144) and decrease fibrinolytic activity II. Hirsh J. Genton E. Hull R. Thrombolytic drugs. In Ref. 8: 198-208. (125). Estrogen also causes elevations in the level of a 12. Browse NL. Clemenson G. Croft ON. Flbnnogen detectable throm• number of coagulation factors, but this is unlikely to be bosis in the legs and pulmonary embolIsm. Br Med J 1974; I:603-4 important in thrombogenesis (145,146). 13. Browse NL, Lea Thomas M. Source of nonlethal pulmonary embolI. Other clinical disorders that predispose to venous Lancet 1974;1:258-9. thromboembolism. Other conditions that have been re• 14. Shull KC, Nicolaides AN. Fernandes F. et al. Significance of pop• ported to be associated with venous thromboembolism in• liteal reflux In relation to ambulatory venous pressure and ulceralion. Arch Surg 1979;1 14:1304-18 clude thrombocytosis, polycythemia vera and systemic lu• 15. Kakkar VV, Howe CT. Nicolaides AN. Renney JIG. Clarke MB. pus erythematosus. When thrombocytosis occurs after Deep vein thrombosis of the leg. Is there a "high risk group"? Am splenectomy or other surgical procedures, it is transient and J Surg 1970;120.527-30. not associated with an increased risk of venous thrombosis 16. Corrigan TP. Fossard DP. Splnder T, et al. Phlebography in the (147,148). In contrast, thrombocytosis associated with mye• management of pUlmonary embolIsm. Br J Surg 1974;61:484-8. loproliferative disorders such as polycythemia vera (149) or 17. Freiman DG. The structure of thrombI. In: Colman RW, Hirsh J, Marder V. Salzman EW. eds. ThrombOSIS and HemostasIs. Basic with splenectomy in patients with sideroblastic anemia and Principles and Clinical Practice. Phtladelphia: JB Lippincott. other hemolytic anemias has been reported to be associated 1982:766-80. with an increased frequency of venous thromboembolism 18. Kakkar VV, Flanc C, Howe CT, Clarke MB. Natural history of (147). The mechanism of this increased tendency for throm• postoperative deep vein thrombOSIS. Lancet 1969,2:230-2. bosis is uncertain, but may be due to the effect ofhyperactive 19. Nicolaides AN, Kakkar VV. Field ES. Renney JTG. The origin of platelets. Patients with polycythemia vera have the addi• deep vein thrombosis: a venographic study. Br J Radiol 1971 ;44: 653-63. tional risk factor of high blood viscosity, which also occurs 20. Stamatakis JD, Kakkar VV, Sagar S, et al. Femoral vein thrombusis in patients with erythrocytosis due to chronic anoxia. and total hip replacement. Br Med J 1977;2:213-5. Patients with systemic lupus erythematosus may have 21 Hirsh J. Genton E. Thrombogenesis. In: Physiolugical Pharmacol• recurrent episodes ofsuperficial deep vein thrombosis (150). ogy. New York: Academic Press. 1974:99-133. Recently, immune complexes directed' against endothelial 22. Wessler S, Yin ET. On the mechanIsm of thrombOSIS. In: Brown cells have been described in patients with systemic lupus EB. Moore CV, eds. Progress in Hematology. 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25. Borgstrom S. Gelin LE. Zenderfeldx B. The fonnation ofvein thrombi 47. Osterud B. Rapaport SI. Activation of factor IX by the reactIon following tissue injury. Acta Chir Scand 1959;247(suppl):8-14. product of tIssue factor and factor VIII: additional pathway for im• 26. Moschos CB. Khan MI. Regan TJ. Thrombogenic properties ofblood tIating blood coagulation. Proc Natl Acad Sci USA 1977;74:5260-4. during early ischemIc and non-IschemIc mjury. Am J Physiol 48. Walsh PN, Griffin JH. Contributions of human platelets to the pro• 1971 ;220: 1882-4. teolytic activatIon of blood coagulation factors XII and XI. Blood 27. Bjorklid E. Giercksy KE, Prydz H. An immunoradiometric assay 1981 ;57: 106-18. for factor III (tissue thromboplastin). Br J Haematol 1978;39:445-8 49. Wilner GO, Nossel HL, Leroy EC. ActIvatIon of Hageman factor 28. Davie EW, Fujikawa K, Kurachi K, Kisiel W: The role of serine by collagen. J Clin Invest 1968;47:2608-15. protease in the blood coagulation cascade. 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In patients with fracture of the upper end of the femur J Bone JOInt 94 von Kaulla E, von Kaulla KN DefiCiency of antlthrombm III activity Surg 1970;52B:268-89. associated with heredllary thrombOSIS tendency J Med (Ba,e I) 71. Harrb WH, Salzman EW, AthansoulIs CA, et al Aspirin prophylaxb 1972,3:349 of venous thromboembolism after total hlp replacement N Engl J 95. Buonassisi V. Sulfated mucopolysaccharide syntheSIS and secretion Med 1977,297.1246-9. m endothelIal cell cultures. Exp Cell Res 1973;76.363-8 72. Hume M, Turner RH, Kuriakose TX, Surprenant J. Venous throm• 96. Telen AN, Abllgaard U, Hook M. The anticoagulant effect ofheparan bosis after total hip replacement. J Bone Joint Surg 1976;58:933-9. sulfate and dermatan sulfate. Thromb Res 1976;8'859-67. 73. Hampson WGJ, Hams FC, Lucas HK, et al. Failure of low-dose 97. Kasper CK. 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117. Blatt PM, Lundblad RL, Kingdon HS. et al. Thrombogenic materials 134. Isacson S, Nilsson 1M. Defective fibrinolysis in blood and vem walls in prothrombin complex concentrates. Br J Haematol 1977;36:573. in recurrent "idiopathic" venous thrombosis. Acta Chir Scand 118. Castellino FJ, Violand BN The fibrinolytIC system-basIc consid• 1972;138:313-9. erations. Prog Cardiovasc DIs 1979;21 :241-54. 135. Johansson L, Hedner U, NIlsson 1M. A family with thromboembolic 119 Wiman B, Collen D On the mechanIsm of the reaction between disease assOCiated With deficient fibnnolytlc activity in vessel wall. human alpha-2-antiplasmin and plasmin J BioI Chern 1979;254: Acta Med Scand 1978;203:477-80 9291-7. 136 Jarrett PEM, Morland M, Browse NL. Idiopathic recurrent superficial 120. Comp pc, Jacocks RM, Taylor FB Jf. The dilute whole blood clot thrombophlebitis: treatment with fibrinolytic enhancement. 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