Pathogenesis of Venous Thrombosis· Eberhard F. Mammen, M.D.

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enous thromboembolism, ie, venous thrombosis and pulmonary embolism, represents a serious and potentially fatal complication for many sick, hospitalized patients, especially those who are bedridden for extended periods of time. But even nonhospitalized, ambulant patients and apparently healthy individuals may encounter this problem. The magnitude of this complication is difficult to assess since many venous thromboses and pulmonary emboli are clinically silent. In part, this is due to the lack of sensitivity and specificity of clinical diagnostic efforts. The diagnosis is highly dependent on the diagnostic procedures applied, and it is estimated that only 1% of the venous thromboses are clinically recognized. The incidence of fatal pulmonary embolism has been estimated as 200,000 patients annually in the United States alone.' There are a number of clinical risk factors that have been associated with a high incidence of venous thromboembolism (Table 1). Many entail altered blood flow conditions, others altered blood coagulation in the sense of an increased clotting tendency, also termed hypereoagulability Venous thrombi are basically composed of fibrin and erythrocytes with variable amounts of platelets and leukocytes interwoven." In contrast, arterial thrombi are predominantly composed of platelets with fibrin interwoven. 3 The development of venous thrombosis is greatly influenced by altered blood flow conditions. Most thrombi form in regions of slow or disturbed flow They arise initially as small fibrin deposits in the large venous sinuses of the calf or in valve cusp pockets in the deep veins of the calf or thigh. 4 Alternatively; they may develop in venous segments that have been exposed to trauma." The initial fibrin nidus will grow by apposition leading to more and more occlusion of venous segments, as schematically illustrated in Figure 1. Hemodynamic and thus, clinical symptoms will only then appear when large enough vessels are affected. This explains in part why the clinical diagnosis can only be established in about 1% of all patients who have thrombosis established by other procedures. When Virchow" formulated his concept of the pathogenesis of thrombosis, especially venous thrombosis, he postulated that 3 factors would be offundamental importance: (1)vessel wall damage; (2) blood flow changes; and (3) alterations in the blood. This triad of Virchow still today can be used as a basis for the understanding of the development of thrombosis. Experimentally and clinically, it is now recognized that at least 2 of these 3 postulated factors in combination are important in the development of a venous thrombosis, *From the Departments of Pathology, Obstetrics and Cynecology; and Physiology, Wayne State University School of Medicine, Detroit. Reprint requests: Dr. Mammen, Mott Center; 275 East Hancock, Detroit48201

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whereby decreased blood How or stasis seems to be the dominant component. In a rabbit model, it was experimentally shown that venous stasis alone was insufficient to produce a thrombus. However, when venous stasis was combined with either vessel wall damage or increased blood coagulability, a thrombus would form." Clinically, the role of vessel wall damage in the pathogenesis of venous thrombosis is uncertain at this time, but immobility plus increased coagulability is recognized as a major risk factor. Immobility brings about decreased blood How by a lack of muscle contraction, and thus, a lack of the pumping action of the large muscle packages of the legs on venous blood How As a consequence, blpod pools in the intramuscular sinuses of the calf," This pooling increases blood coagulability because activated clotting factors and activation products of coagulation accumulate locally; and blood coagulation inhibitors are locally consumed. This process may be exacerbated by the autocatalytic activation of the coagulation system" leading to further hypercoagulabili~ In addition, there is dilation of the leg veins with reduced venous capacitance. 10 There is the possibility that this dilation is associated with endothelial damage, and thus, fibrin nidus formation." IMMOBILITY AND ALTERED BLOOD FLOW

The importance of immobility in the pathogenesis of venous thrombosis can be illustrated by several of the following clinical examples: 1. Spinal cord injury patients with paralysis are at high risk for developing deep venous thrombosis. The overall incidence is stated from 50% to 100%, depending on the methods used for determination. lJ-14 There is little relationship to other risk factors and both limbs are affected. 2. A comparison of 2 small groups of spinal cord injury patients, one with paralysis the other without, gave a 100% incidence of deep venous thrombosis in the paralyzed group, but none in the nonparalyzed patients. 15 3. In acute stroke patients, the paralyzed limbs had a Table I-BiBle FtJcton for Venous Thromboembo_ Surgery and other trauma Previous thromboembolism Prolonged immobility and paralysis Malignancy

Congestive heart failure Obesity Advanced age (>40) Pregnancy and puerperium Varicoseveins Oral contraceptives (?) Hypercoagulability Pathogenesis of Venous Thrombosis (Eberhard F. Mammen)

FIGURE 1. Schematic representation of the development of a venous thrombus. Small 6brin deposits develop in valve cusp pockets (A). These grow by apposition (8 + C) to occlude more and larger venous vessel segments.

63% rate of thrombosis as compared to only 7% in the

nonparalyzed limb. Ie 4. An autopsy study revealed a relationship between bedrest and venous thrombosis. Patients confined to bed for more than 1 week had a considerably higher incidence than those who were bedridden for less than one week. 17.18 5. Preoperative immobility was associated with a higher postoperative incidence of deep venous thrombosis. Ii 6. Postoperative patients remain at higher risk during the entire period of immobility, especially if they remain immobile after discontinuation of thrombosis prophylaxis. lID 7. Patients with fractures of the lower limbs are at high risk for developing venous thrombosis when the limbs are immobilized by a plastic cast." . 8. The use of external compression modalities as prophylaxis in high risk patients yields a major reduction in the development of venous thrombosis. II The devices not only prevent stasis but also apparently activate the fibrinolytic system. Stasis due to venous obstruction may also be encountered in patients with previous venous thrombosis, patients with pelvic tumors, and in women during their last trimester of pregnancy 13 Raised venous pressure with subsequent decreased blood flow could be the predisposing factor for the high incidence of deep venous thrombosis in patients with heart failure." Blood flow could also be influenced by changes in blood viscosity,· since viscosity increases in areas of slow flow Viscosity is increased in a variety of disease states such as conditions with increased hematocrit values and dysproteinemias. Patients with inflammatory diseases may have increased fibrinogen levels. Since fibrinogen is an acute phase reactant protein, and since it is markedly increased in patients with spinal cord injury and paralysis, 13 this factor together with dehydration, could potentially also contribute to an increased risk for deep venous thrombosis. Immobility due to paralysis of spinal cord injury patients is undoubtedly one of the major contributing factors for the development of deep vein thrombosis. The lack of muscular pumping leads to pooling of blood in the venous sinuses of the calf with the potential of activation of the coagulation system due to accumulation of activation products and consumption of inhibitors. Decreased blood flow could be

exacerbated by hyperviscosity secondary to dehydration and elevations in fibrinogen levels. VESSEL WALL DAMAGE

Vessel wall damage in the development of venous thrombosis is at present uncertain, unless venous distension, as indicated above, indeed leads to endothelial damage. Microscopic vessel wall damage has so far only been found in patients undergoing hip or knee replacement surgeries," and both procedures are associated with a high incidence of postoperative deep venous thrombosis. It has also been documented in patients with lower limb trauma and burn patients." Vessel wall damage, macroscopically or rnicroscopically, has so far not been found in patients subjected to other forms of surgery although these patients may also have a high risk of developing deep venous thrombosis. little or nothing is known about nonvisible, possibly metabolic damages to the endothelium. While this is plausible, no evidence has as yet been gathered. In the last few years, it has become evident that the endothelial lining of the vasculature is more than a mere smooth lining which prevents platelet interaction with subendothelial vessel wall structures. A number of receptors have been identified, especially heparin-like glycosaminoglycans that seem to be of great importance in providing the noninjured endothelium with a strong anticoagulant posture. As endothelial cells are perturbed, this anticoagulant property changes to a procoagulant posture which aids in the activation of the hemostasis system. TIssue factor will be released, platelets will adhere and aggregate, and the contact system of the intrinsic pathway of clotting will be activated. The interrelationship between impaired blood 80w and metabolic endothelial damage has so far not been studied to any extent. Once the hemostasis system is activated, several links can lead to vessel wall damage. Thrombin induces endothelial injury, 6brin(ogen) split products increase endothelial permeability; platelet release substances increase endothelial permeability, factor XIIa and kallikrein activate the kininogen and complement systems, and elastases released from adhering leukocytes induce further endothelial damage. All of these mechanisms could be operational in cases of venous stasis, but little is known at this time. CHEST I 102 I 8 I DECEMBER, 1992 I Supplement

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Table 2-Hemosta3ia Abnormalitiea Prediapoaing to Thromboembolic Disorder. Congenital abnormalities:

! Protein C ! Protein S ! Antithrombin III ! Plasminogen ! t-PA release t PAl-l

Acquired abnormalities :

Above Anticardiolipin-associated syndromes

Vessel wall damage may be encountered in paralyzed spinal cord injury patients either directly by the trauma that led to the cord injury or indirectly by external pressure on the immobile leg. Blood pooling could lead to vein wall distension with endothelial damage, and metabolic damage to the endothelial lining could be an additional but not yet well investigated mechanism. Once the hemostasis system is activated, thrombin, release products from platelets, and end products of fibrinolysis could enhance vascular damage . ALTERATIONS IN THE BLOOD

Virchow is frequently credited with having postulated increased coagulability of the blood. At the time Virchow postulated his triad, very little was known about blood coagulation, and certainly, hypercoagulability was not understood. The proposed "alterations in the blood" were associated with blood coagulation considerably later. The blood coagulation system, composed of the clotting and the fibrinolytic system, is apparently continuously operational, although in a subliminal mode . Therefore, there must be a physiologic equilibrium between clotting and fibrinolysis. Any major imbalance can either be associated with a bleeding or a thrombosing tendency. ".17 A hyperactive clotting system or an inhibited fibrinolytic system seem to predispose to thrombosis, predominantly venous thromboembolism. Increased clotting or thrombin generation seems to occur when there is diminished inhibition. Abnonnalities, congenital or acquired, of antithrombin III and the protein C and S system are the best known examples of such an imbalance" (Thble2). The best known changes in the fibrinolytic system associated with an increased risk of thrombosis are abnonnalities of plasminogen, decreased endothelial release of tissue plasminogen activator (tPA), and elevated levels of the inhibitor of tPA, plasminogen activator inhibitor (PAl-I) (Table 2). A frequently encountered acquired abnonnality associated with predominantly venous thromboembolism is the so-called "anticardiolipin-associated syndrome;' also known as "lupus anticoagulant:' The association of this laboratory abnonnality with the increased thrombosing tendency is presently not understood." All of the patients with anyone of the abnonnalities listed in Thble 2 have a clear predisposition to an increased risk of thromboembolic disease. From patients with congenital abnonnalities it is known, however, that the existence of the defect alone does not necessarily "cause" a thrombosis. Many family members may be asymptomatic until a major

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challenge is encountered to the coagulation system . This may be in the fonn of a major surgical procedure, trauma, childbirth, or possibly upon ingestion of oral contraceptive medications. The congenital abnonnalities are rare but must be suspected when patients have a strong personal or family history of recurrent thromboembolic disorders. Most investigations on the "alterations in the blood" have been performed on surgical patients since major surgeries are associated with a considerable risk of postoperative deep venous thrombosis and pulmonary embolism . The postoperative risk in surgical patients is related to the extent of the SUrgical trauma, the site of surgery, the length of the procedure, and the length of time patients remain immobilized postoperatively. 18.111.30 Orthopedic surgery, especially hip and knee replacement, is associated with the highest risk of postoperative deep venous thrombosis," The majority of thromboses are found in the operated limb. Similar high risk is found in patients with extensive malignant disease who are subjected to extensive surgery. The following 3 major thrombogenic factors have been associated with surgery and trauma: (1) release of procoagwant material during surgery; (2) preoperative, perioperative, and postoperative immobility, and (3) reduced postoperative fibrinolytic activity (fibrinolytic shutdown). The release of tissue thromboplastin during surgery has been suggested as a cause of intraoperative hypercoagulability.3O We have addressed this issue" with the use of newer techniques, called molecular markers of hemostasis activation. With these methods, actual end products of clotting or fibrinolysis can be measured. Certain hemostasis parameters were measured during elective hip replacement and up to 48 h postoperatively. As demonstrated in Figure 2, there

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B..ECTlVE HIP REPLACEMENT lftal5l FIGURE 2. Measurement of antithrombin III (ATIII), a.-antiplasmin (asAP)and thrombin/antithrombin III complexes (rAT3)in patients subjected to elective hip replacement. Both inhibitors decrease during the procedure while TAT3 complex levels peak when the artificial hip is placed. It appears that there is, at this time , a maximal activation of the clotting system .

PathogenesIs of Venousthrombosis (Eberhard F. Mammen)

is not only a drop in antithrombin III and as-antiplasmin during surgery; but a significant rise in thrombin/antithrombin III (TAT) complexes. The TAT complex levels were highest when the artificial hip was placed, suggesting a marked activation of the coagulation system at that time. This could very well be the time where the nidus for the venous thrombus is laid, aided by the immobility of the patient on the operating table. It has generally been suggested that the nidus for postoperative venous thrombosis is laid intraoperatively This suggests that prophylactic measures should begin preoperatively and be continued perioperatively and postoperatively Considerable work has been performed, especially in the Scandinavian countries, on the 6brinolytic system of patients with deep venous thrombosis. Euglobulin lysis times and venous occlusion techniques have been employed coupled with the quantitative measurements of tPA and PAl-I. Decreased 6brinolytic activity has been observed in many patients in the early postoperative period34 and in several other conditions associated with an increased thrombosing tendency," Less fibrinolytic activity has been found in leg vein tissues when compared to arm vein tissues," and an association between decreased 6brinolytic activity and postoperative deep vein thrombosis has been suggested." In a large series of patients with recurrent idiopathic venous thrombosis, 70% had impaired release of tPA upon venous occlusion." This association is probably more prevalent than any other abnormality of the hemostasis system." Also, preoperatively prolonged euglobulin lysis times were associated with a higher risk of postoperative venous thrombosis in gynecologic patients," Similar data were described for recurrence rates of thrombosis," These studies did not elucidate the potential changes in tPA release or PAl-1 levels as reasons for the prolonged euglobulin lysis times. Increased PAI-I levels have not only been described in patients with acute myocardial infarction and reinfarction," but also in patients with recent venous thrombosis," The latter was not confirmed, however, in a prospective stud~"" In a study of patients subjected to hip replacement, elevated preoperative PAI-I levels were associated with deep vein thrombosis." This againwas not found in patients undergoing abdominal surge!"}:46 It is apparent that there is still no uniform opinion on the role of the individual components of the 6brinolytic system in venous thromboembolism, although increased 6brinolytic activity preoperatively seems to be associated with less postoperative thrombosis," It is also unclear at this time whether some of the changes seen in patients with existing deep venous thrombosis led to the thrombosis or whether they were a reflection of the thromboembolic event. In our own experience, elevated PAI-I levels are the most frequently observed laboratory abnormality in patients with venous thromboembolic disease. These fibrinolytic parameters were also studied in a small group of spinal cord injury patients with and without paralysis," Patients with thrombosis had higher PAl-1 values than those without paralysis and thrombosis, but again, it is not clear whether this 6nding was causally related to the thrombosis or a consequence thereof: Paralyzed spinal cord injury patients develop a number of changes in their hemostasis system. These include elevated 6brinogen levels, increased concentrations of the

components of the von Willebrand factor macromolecular complex, and increased platelet aggregation.•3 ••4.48 These changes develop shortly after injury and persist over a 2- to 3-week time span. During this time, most thromboses are detected. Alterations in fibrinolysis (elevated PAI-I levels) have more recently been added" as potential factors associated with the thrombosis in paralyzed patients. Again, it is not fully understood whether these changes are causally related or a consequence of the developed thrombotic process. SUMMARY

This brief review attempts to describe the present understanding of the pathogenesis of venous thrombosis in general with special reference to venous thromboembolism in spinal cord injury patients with paralysis. The component parts of Virchows triad are examined. Most venous thrombi seem to originate in regions of slow blood 80~ ie, the large venous sinuses of the calf and thigh or in valve cusp pockets. Decreased blood flow or even stasis due to lack of the pumping action of the large muscle packages in paralyzed patients is undoubtedly one of the major factors. As blood pools, activation products of the coagulation system accumulate locally leading potentially to local hypercoagulability. Activation products of clotting and 6brinolysis can induce endothelial damage which in turn leads to further activation of the hemostasis system. Endothelial damage may also result from distension of the vessel walls by the pooling blood. Blood flow is further decreased by hyperviscosity due to elevated 6brinogen levels and dehydration. Some spinal cord injury patients may sustain direct trauma to the legs; others may encounter vessel wall damage by the immobilized limbs. Shortly after injury, certain changes develop in the clotting system, especially increases in components of the von Willebrand factor macromolecular complex and increased platelet aggregability which could further contribute to hypereoagulability Recently an inhibition of the fibrinolytic system was suggested which also could add to a prothrombotic state. All of these interrelated processes clearly explain the high risk of venous thromboembolism in spinal cord injury patients with paralysis which has been clearly demonstrated by many investigators. It is hoped that intense thrombosis prophylaxis will reduce the incidence of this potentially devastating complication. REFERENCES

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8 Almen T, Bylander G. Serial phlebography of the normal leg during muscular contraction and relaxation. Acta Radiol 1962; 57:264-72 9 Davie E~ Fujikawa K, Kurachi K, et al. The role of serine proteases in the blood coagulation cascade. Adv Enzymoll979; 48:277-318 10 Tripolitis AJ, Bodily KC, Blacksheer WM, et aI. Venous capacitance and outflow in the postoperative patient. Ann Surg 1979; 190:637-43 11 Schaub RD, Lynch PR, Stewart GJ. The response of canine veins to three types of abdominal surgery: a scanning and transmission electronic microscopic study. Surgery 1977; 38:179185 12 Todd J~ Friesbie JH, Rossier AB, et aI. Deep venous thrombosis in acute spinal cord injury: a comparison of ItsI fibrinogen leg scanning, impedance plethysmography and venography Paraplegia 1976; 14:50-57 13 Rossi EC, Green D, Rosen JS, et aI. Sequential changes in factor VIII and platelets preceding deep vein thrombosis in patients with spinal cord injury. Br J Hematoll980; 45:143-51 14 Petaja J, Myllynen ~ Rokkanen ~ et aI. Fibrinolysis and spinal injury: relationship to post-traumatic deep vein thrombosis. Acta Chir Scand 1989; 155:241-46 15 Myllynen ~ Kammonen M, Rokkanen ~ et aI. Deep venous thrombosis and pulmonary embolism in patients with acute spinal cord injury: a comparison with nonparalyzed patients immobilized due to spinal fractures. J Trauma 1985; 25:541-43 16 Warlow C, Ogston D, Douglas AS. Venous thrombosis of the legs after stroke. BMJ 1976; 1:1178 17 Gibbs NM. Venous thrombosis of the lower limbs with particular reference to bed-rest. Br J Surg 1957; 5:209-11 18 Sevitt S, Gallagher NG. Venous thrombosis and pulmonary embolism: a clinico-pathological study in injured and burned patients. Br J Surg 1961; 48:475-89 19 Sigel B, Ipsen J, Felix WR. The epidemiology of lower extremity deep venous thrombosis in surgical patients. Ann Surg 1974; 179:278-90 20 Gallus AS, Hirsh J, O'Brien SE, et aI. Prevention of venous thrombosis with small subcutaneous doses of heparin. JAMA 1976; 235:1980-82 21 Hamilton H~ Crawford JS, Gardiner JH, et aI. Venous thrombosis in patients with fracture of the upper end of the femur. J Bone Joint Surg 1970; 52:268-89 22 Caprini JA, Scurr JH, Hasty JH. Role of compression modalities in a phrophylactic program for deep vein thrombosis. Semin Thromb Hemost 1988; 14:(suppl)77-87 23 Hull RD, Carter CJ, Jay RM, et aI. The diagnosis of acute recurrent deep vein thrombosis: A diagnostic challenge. Circulation 1983; 67:901-06 24 Simmons AY, Sheppard MA, Cox AF. Deep venous thrombosis after myocardial infarction: Predisposing factors. Br Heart J 1973; 35:623-25 25 Leonard EF. Rheology of thrombosis. In: Coleman ~ Hirsh J, Marder VJ, et al, eds. Hemostasis and thrombosis: basic principles and clinical practice. 2nd Ed. Philadelphia: JB Lippincott, 1987; 1111-22 26 Salem HH, Mitchell CA, Firkin BG. Current views on the pathophysiology and investigations of thrombotic disorders. Am J Hematoll987; 25:463-74 27 Mammen EF, Fujii Y. Hypercoagulable states. Lab Med 1989; 20:611-16 28 Triplett DA, Brandt IT. Lupus anticoagulant: misnomer, para-

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dox, riddle, epiphenomenon. Dematol Patholl988; 2:121-43 29 Kakkar ~ Howe Cl: Nicolaides AN, et al. Deep vein thrombosis of the legs: is there a "high-risk' group? Am J Surg 1970; 120:527-30 30 Bergqvist D. Postoperative thromboembolism: frequency, etiology, prophylaxis. Berlin: Springer, 1983 31 Planes A, Vochelle N, Bouthier J, et aI. Use of enoxaparin, a low molecular weight heparin, in elective hip surgery Semin Thromb Hemost 1991; 17(suppl 3):296-303 32 Bjorldid E, Giercksy KE, Prydz H. An immunoradiometric assay for factor III (tissue thromboplastin). Br J Haematoll978; 39:445-58 33 Mammen EF. The risk of thrombosis associated with surgery Clin Diag Lab Med 1989; 2:41 34 Comp PC, Jacocks RM, Taylor FB Jr. The dilute whole blood clot lysis assay: a screening method for identifying postoperative patients with a high incidence of deep venous thrombosis, J Lab Clin Med 1979; 93:120-27 35 Hirsh J, Salzman EW Pathogenesis of venous thromboembolism. In: Coleman ~ Hirsh J, Marder VJ, et al, eds. Thrombosis and hemostasis: basic principles and clinical practice. 2nd Ed. Philadelphia: JB Lippincott, 1987; 1199-1207 36 Robertson BR, Pando16 M, Nilsson 1M. Fibrinolytic capacity in healthy volunteers at different ages as studied by standardized venous occlusion of arms and legs. Acta Med Scand 1972; 191:199-202 37 Crandon AJ, Peel KR, Anderson JA, et al. Postoperative deep vein thrombosis: Identifying high-risk patients. Br Med J 1980;

291:343-44 38 Isacson SI, Nilsson 1M. Defective fibrinolysis in blood and vein walls in recurrent idiopathic venous thrombosis. Acta Coo Scand 1972; 138:313-19 39 Lijnen HR, Collen D. Congenital and acquired deficiencies of components of the fibrinolytic system and their relation to bleeding and thrombosis. Fibrinolysis 1989; 3:67-77 40 Rakoczi I, Chamone D, Collen D, et ale Prediction of postoperative leg vein thrombosis in gynaecological patients. Lancet 1978; 1:509-10 41 Korninger C, Lechner K, Niessner H, et aleImpaired fibrinOlytic capacity predisposes for recurrence of venous thrombosis. Thromb Haemost 1984; 52:127-30 42 Hamsten A, de Fair U, Walldius G, et ale Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2:3-8 43 Wiman B, Chmielewska J. A novel fast inhibitor to tissue plasminogen activator in plasma, which may be of great pathophysiological significance. Scand J Clin Lab Invest 1985; 45:(suppl)43-47 44 Mellbring G, Dahlgren S, Wiman B, et ale Relationship between preoperative status of the fibrinolytic system and occurrence of deep vein thrombosis after major abdominal surgery Thromb Res 1985; 39:157-63 45 Paramo jA, Alfaro MJ, Rocha E. Postoperative changes in plasmatic levels of tissue-type plasminogen activator and its fastacting inhibitors: relationship to deep vein thrombosis and influence of prophylaxis. Thromb Haemost 1985; 54:713-16 46 Mellbring G, Dahlgren S, Wiman B. Plasma fibrinolytic activity in patients undergoing major abdominal surgery. Acta Chir Scand 1985; 151:109-14 47 Mellbring G, Dahlgren S, Reiz S, et al. Fibrinolytic activity in plasma and deep vein thrombosis after major abdominal surgery. Thromb Res 1983; 32:575-84 48 Myllynen ~ Kammonen M, Rokkanen ~ et al, The blood F.VIII:A'IfF. VIII:C ratio as an early indicator of deep vein thrombosis during posttraumatic immobilization. j Trauma 1987; 27:287-90

Pathogenesis of Venous Thromboeia (Eberhard F. Mammen)