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Acs0606 Venous Thromboemboli

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  • 1. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 1 6 VENOUS THROMBOEMBOLISM John T. Owings, M.D., F.A.C.S. Deep vein thrombosis (DVT) (deep thrombophlebitis) occurs in tionated heparin subcutaneously as prophylaxis against DVT fared approximately 2.5 million people in the United States each year.1 no better than those treated with placebo.15 Subsequent work has The incidence of DVT in surgical patients varies widely depend- shown that effective DVT prophylaxis can be achieved in this pop- ing on the method of study: in eight series, the incidence of DVT ulation by using the LMWH enoxaparin. verified by venography or autopsy ranged from 18% to 90% (aver- COMPRESSION TECHNIQUES age, 42%).2 Reviews suggest that pulmonary embolism (PE) occurs in Elastic stockings have long been used as prophylaxis for throm- approximately 700,000 people in the United States each year, of boembolism. Most commercial stockings, however, do not fit ade- whom about 200,000 will die as a result.3,4 In the absence of pro- quately or provide adequate compression and thus probably offer phylaxis, fatal PE occurs in 4% to 7% of hip surgery patients and little or no benefit.4 Low-molecular-weight dextran, which lowers in 0.1% to 0.8% of general surgery patients.3,5 In 40% to 60% of blood viscosity and inhibits platelet aggregation, may be helpful in patients who die of PE, the diagnosis is not made clinically. PE may certain instances, but data showing greater efficacy as compared be responsible for as many as 5% of postoperative deaths, and it with current techniques are lacking.12 may occur in as many as 25% of patients admitted to the hospi- Pneumatic devices that compress the venous plexuses of the tal.6,7 Pulmonary infarction occurs in about 10% of PE patients.8 lower extremities are popular because they do not require antico- Significant PE is believed, as a rule, to arise from thrombosis of agulation and thus are not associated with increased bleeding risk. the deep veins of the thigh and the pelvis. Most studies of throm- Intermittent pneumatic compression is capable of intermittently boembolism use DVT as a surrogate end point for PE. The only increasing venous flow velocities in the femoral and pelvic veins.16 major study of thromboembolism prophylaxis to date that suc- It has been argued that some of the benefit might derive from the cessfully used death from PE as an end point required more than known tourniquet effect of enhancing fibrinolytic activity, attrib- 5,000 patients to reach statistical significance.9 Accordingly, the uted both to an increase in tissue plasminogen activator (t-PA) and National Institutes of Health has concluded that using DVT as a to a decrease in plasminogen activator inhibitor (PAI). This argu- surrogate for PE is a valid approach.10 ment seems to be valid for up to 24 hours of continuous use,17 but The optimal treatment of thromboembolism is prevention, par- after that point, the effect is exhausted.16 Intermittent pneumatic ticularly in persons at high risk [see Table 1].11,12 Risk factors for compression is a safe, albeit somewhat uncomfortable, method of venous thromboembolism include increased age (≥ 30 years in preventing clots in patients immobilized for prolonged periods. It some studies),13 major trauma (Injury Severity Score of 15 or is particularly useful in critical care units, where other forms of greater or the presence of a pelvic or lower-extremity long bone prophylaxis are inapplicable or contraindicated.11 fracture), morbid obesity, major operation, prolonged immobility, Several different pneumatic compression devices have been thrombophilia, and previous thromboembolism. developed. The first to gain widespread acceptance was the full- length (calf and thigh) sequential compression stocking, which proved effective in a number of settings, including trauma.18 Prophylaxis against Thromboembolism In evaluating the effectiveness of the methods used to prevent thromboembolic complications, it is important to consider the spe- Table 1—Risk Factors for the Development cific population of patients studied. Within the surgical patient population, there is one reasonable division: between (1) patients of Venous Thromboembolism who have an ongoing pathologic process that affects coagulation Hypercoagulability when first encountered and (2) elective patients for whom the sur- Congenital hypercoagulability gical insult is the inciting risk factor. For the first group, the typi- Malignancy cal patient is the polytrauma patient; for the second, the patient Oral contraceptives undergoing elective hip or knee replacement. Polycythemia The key distinction between these two groups lies in whether Thrombocytosis prophylaxis can be given before the inciting insult. Several tech- Venous stasis niques for prophylaxis of thromboembolism that are effective when Immobility employed before the inciting event are completely ineffective if Varicose veins employed afterward. This point can be illustrated by comparing Advanced age elective colorectal surgery patients with trauma patients. In a 2001 Congestive heart failure study, elective colorectal surgery patients who were given their first Obesity dose of unfractionated heparin before operation and then were given additional doses of unfractionated heparin (5,000 units sub- Endothelial injury cutaneously three times daily) after operation were as well protect- Trauma ed against DVT as comparable patients receiving low-molecular- Recent surgery weight heparin (LMWH) and were at lower risk for bleeding.14 In Severe infection a 1996 study, however, trauma patients who were given unfrac-
  • 2. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 2 Because some injured patients were unable to wear the device, var- heparin two or three times daily before, during, and after the oper- ious modified compression devices were developed, including a ation substantially reduced thromboembolic complications with- calf-only device and a foot pump designed to compress the plan- out increasing bleeding.5 This low-dose protocol has been criti- tar venous plexus. Several studies have demonstrated that the var- cized as being insufficiently individualized for specific high-risk ious compression devices are not all equally effective in preventing patients. Low-dose heparin acts by markedly augmenting the thromboembolism. This is an important point because many of antithrombotic effect of antithrombin21; therefore, it may be inef- the devices are marketed solely on the basis of compliance data fective if antithrombin levels are reduced, and higher doses may be rather than efficacy data; those that are marketed without pub- more appropriate in such settings. lished evidence of efficacy often use cost advantages to gain mar- Because of these pitfalls, an adjusted-dose technique was ket share. devised in the mid-1980s.22 In this method, heparin is given The effectiveness of pneumatic compression devices is based on (either subcutaneously or I.V.) in sufficient doses to elevate the their ability to increase peak venous flow velocity in the large ves- activated partial thromboplastin time (aPTT) by 2 to 5 seconds, sels of the thigh and the pelvis. Because some units create higher thereby compensating for depleted antithrombin levels in high- peak flow velocities, it would be logical to assume that these units risk patients. This technique is superior to the low-dose method would be more effective in reducing DVT. Support was lent to this for preventing venous thromboembolism,22 and for practical pur- assumption by a 2000 study in which more than 300 patients poses, it should replace the latter as the standard prophylactic dos- undergoing elective knee surgery were treated with different com- ing technique for unfractionated heparin.22,23 pression devices.19 Devices applying asymmetrical compression LMWH possesses the same antithrombin-potentiating penta- (which results in higher peak venous flow velocity) were compared saccharide chain that unfractionated heparin does. Consequently, with traditional compression devices, and calf-only devices were it is similarly ineffective if antithrombin levels are depleted. The compared with calf-and-thigh devices. The two calf-and-thigh main advantage of LMWH over unfractionated heparin is that it units studied proved superior to the calf-only unit, and the calf- has a more dependable half-life and bioavailability.Thus, it can be and-thigh asymmetrical sequential compression device that gener- given without monitoring of drug effect or plasma heparin level. ated higher peak flow velocities was superior to the traditional calf- Most of the clinical trials documenting the efficacy of LMWH and-thigh device. Similar results were obtained in a 2004 study evaluated patients undergoing elective hip24,25 or knee operations. that compared knee-high compression devices.20 A few, however, addressed other patient populations (e.g., trauma It is therefore important to recognize that although compliance patients).15 In these studies, the incidence of DVT in patients is a critical component of compression devices, differences in effi- receiving unmonitored LMWH therapy was generally lower than cacy must be taken into account. Given the absence of efficacy that in patients receiving placebo24 or low-dose heparin.15,25 data for many of the compression devices now in use, great cau- LMWH therapy and adjusted-dose heparin therapy were of tion should be exercised in considering whether these products roughly equal efficacy. should be adopted, regardless of anticipated cost savings. In the light of these data, it appears that LMWH can be recom- mended over low-dose unfractionated heparin in elective, emer- PROPHYLACTIC ANTICOAGULATION gency, and trauma patients.Whether it is superior to adjusted-dose A major study of thromboembolic prophylaxis in hip surgery unfractionated heparin therapy remains uncertain, though it is patients found that subcutaneous administration of 5,000 units of clearly simpler to manage.Where compliance with monitoring and Manifestations of superficial thrombophlebitis (e.g., pain, slight swelling over vein, erythema, some edema in adjacent tissues) are present. (A palpable subcutaneous cord is pathognomonic.) One limb is at least several centimeters There has been no invasion in or The vein has been invaded, or there are larger than the other near the vein systemic manifestations of infection Assume associated DVT and treat Assume sterile thrombophlebitis; Assume septic thrombophlebitis; initiate therapy. accordingly [see Figures 2, 4, 5, and 6]. initiate therapy. Do not immobilize Remove and culture I.V. catheter. patient. Administer aspirin (1 tablet/day) If there are no systemic signs of infection, treat or dipyridamole (50 mg q.i.d.). as for sterile thrombophlebitis. If systemic signs are present, give antibiotics (antistaphylococcal agents if skin organism is responsible). If patient is a drug addict or has a contaminated wound, obtain Gram stain and culture and initiate specific antibiotic therapy. Phlebitis persists Phlebitis resolves Patient is in toxic state or does Figure 1 Shown is an algorithm not respond to treatment for the management of superficial Interrupt vein above area of thrombosis, thrombophlebitis. or strip and remove vein. Consider ligation or drainage of vein. Consider heparin therapy.
  • 3. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 3 dose-adjusting protocols is an issue, unmonitored LMWH therapy cellulitis and streptococcal lymphangitis. For both conditions, may well be preferable. there should be a proximal source (e.g., an open wound). If there Fondaparinux, a synthetic form of the specific pentasaccharide is overt limb swelling in a patient who appears to have superficial that interacts with antithrombin to potentiate its effect, has been phlebitis, DVT should be assumed and appropriate treatment [see approved by the Food and Drug Administration. This agent is Deep Vein Thrombosis, below] initiated. smaller than the LMWHs and seems to have the same advantages Superficial thrombophlebitis is largely benign but is often over- over these substances that they have over unfractionated heparin— treated out of fear that infection may be contributing to phlebitis. namely, increased bioavailability, longer half-life, and a more con- It is therefore important to differentiate between sterile and septic sistent effect. As the molecular weight of the antithrombin poten- superficial thrombophlebitis. tiator decreases, the antithrombotic effect focuses more sharply on STERILE inhibiting factor X (as opposed to factors II, IX, XII, etc.). Before fondaparinux is uniformly adopted for thromboem- If there is no invasion in or near the superficial vein involved, bolism prophylaxis, the supporting evidence should be carefully sterile thrombophlebitis can be assumed with minimal risk of mis- considered. The initial findings are quite promising. In a prospec- diagnosis. It is best treated simply by giving aspirin (one tablet tive, randomized trial that included approximately 1,700 hip frac- daily) or dipyridamole (50 mg four times daily). ture patients, fondaparinux was superior to enoxaparin with re- If superficial phlebitis of the saphenous vein extends to the spect to the incidence of venographically identified DVT26; how- saphenofemoral junction, interruption of the vein may be appro- ever, the enoxaparin dosage (40 mg once daily) was lower than the priate. The choice of treatment is between interrupting the vein dosage shown to be effective in trauma patients by previous inves- above the area of palpable thrombosis and stripping the vein. The tigators (30 mg twice daily).15 No significant difference in bleeding second alternative carries a higher morbidity but can be effective rates was observed. In another trial, which included approximate- when there are associated varicosities. Stripping of the channels ly 700 patients undergoing elective knee surgery, fondaparinux, above and below the phlebitic process as well as the phlebitic area 2.5 mg once daily, proved superior to enoxaparin, 30 mg twice itself removes the risk of extension and subsequent recurrence. daily.27 In this study, the bleeding rate was significantly higher with Several authors have explored medical management of patients fondaparinux. with above-the-knee superficial thrombophlebitis, using an ap- Ultimately, with regard to prophylactic anticoagulation, simple proach similar to that used for DVT. Therapeutic-dose heparin logic applies. The more potent the anticoagulant used, the lower (unfractionated heparin or LMWH) is given initially, followed by the risk of PE and the higher the risk of serious bleeding. It is there- long-term oral anticoagulation.The incidence of extension may be fore appropriate to base one’s selection of an anticoagulant regi- higher than with surgical management, but the operative risks are men on a careful weighing of the expected benefits against the avoided.30 anticipated bleeding risk. SEPTIC In some patients (e.g., those undergoing major gynecologic pro- cedures), warfarin may be used instead of heparin.12,28 A low-dose If there are systemic manifestations of severe infection, septic regimen (as little as 1 mg/day) may offer some prophylactic bene- thrombophlebitis is likely. In addition, the induration, tenderness, fit.28 Warfarin anticoagulation must be started 3 or 4 days before and redness over and along the course of the vein are usually more the surgical procedure. The international normalized ratio (INR) extensive than with sterile thrombophlebitis. [see General Principles of Anticoagulation and Lytic Therapy, Septic thrombophlebitis associated with an I.V. catheter can be below] should be kept below 3.0 to prevent excessive bleeding. detected by removing the device and culturing the tip. Antibiotics Warfarin is not as easy to regulate as heparin is. In addition, the should be administered. In most cases, antistaphylococcal drugs therapeutic effect takes several days to be realized and several more are appropriate. If the patient is a drug addict or phlebitis is asso- days to wear off. Frequently, postoperative patients are unable to ciated with a contaminated wound, blood samples for culture and resume a normal stable diet. Because warfarin interferes with the Gram staining should be obtained by aspirating the vein. Specific clotting factors in the vitamin K pathway, dosage management in antibiotic therapy directed toward the organisms identified should the immediate postoperative period is challenging. Because the risk then be instituted. of intracranial bleeding is greater with warfarin than with heparin, If the patient is in a toxic state from presumed septic throm- great care should be taken in using warfarin for immediate periop- bophlebitis in a subcutaneous vein or is not responding to treat- erative prophylaxis. ment, it may be appropriate to ligate the vein, to drain it by cutting down on the phlebitic process with the patient under local or gen- PROPHYLACTIC VENA CAVAL INTERRUPTION eral anesthesia and laying the vein open, or to combine ligation Prophylactic vena caval interruption or filter placement provides with drainage. Moist compresses are then applied, the area is prophylaxis only against PE, not against DVT, and thus is dis- immobilized, and antibiotics are administered. Heparin may occa- cussed elsewhere [see Pulmonary Embolism, Minor, Vena Cava sionally be of value, particularly when the process appears to be Filters, below].There is evidence that placement of a vena cava fil- extending into the deep venous system. ter in fact increases the likelihood of DVT.29 Deep Vein Thrombosis Superficial Thrombophlebitis DVT can involve either obstructive clots, which affect drainage Characteristic clinical manifestations of superficial throm- of venous blood from an extremity, or nonobstructive clots, which bophlebitis [see Figure 1] include pain and slight swelling of the are relatively asymptomatic. The latter may be more dangerous extremity, with most of the edema over the course of the involved because such clots are not circumferentially attached to the vein vein. Unless the patient is obese, a palpable, tender subcutaneous wall and thus are more likely to embolize. DVT may be divided cord is usually found (a pathognomonic finding). Erythema may into three main forms: nonocclusive, occlusive, and phlegmasia be present in the overlying skin.The differential diagnosis includes cerulea dolens (massive, limb-threatening DVT).
  • 4. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 4 NONOCCLUSIVE often involves injection of dye not only at the foot or ankle level [see Nonocclusive DVT is common in postoperative and trauma Figure 3] but also at the groin level for visualization of the iliac and patients but all too often is not suspected until an embolic compli- femoral veins. This approach is uncomfortable and is associated cation occurs.31 There may be absolutely no manifestations of clot with morbidity; in critically ill ICU patients, it may not be feasible. on clinical examination, or there may be nonspecific swelling in an Accordingly, noninvasive evaluation techniques are favored. extremity; rarely is there sufficient pain or tenderness to suggest The presence of intravascular clot can be confirmed by detect- DVT. Consequently, it is essential to be aware of the major risk fac- ing D-dimer, a product formed when cross-linked fibrin is broken tors [see Table 1]. down by the fibrinolytic system. Both qualitative and quantitative When DVT develops in an outpatient, every effort should be assays are in current use. The various quantitative assays available made to determine the cause [see Figure 2]. Apparent spontaneous have differing negative predictive values. The gold standard is the onset is often the manifestation of an underlying malignancy or enzyme-linked immunosorbent assay (ELISA) method. Generally, even a congenital clotting tendency that will necessitate lifelong 500 µg/L (in fibrin-equivalent units) or 250 µg/L (in standard treatment [see Hypercoagulability States, below]. Conversely, when units) is an acceptable threshold for a positive result. The latex risk factors for DVT are identified in a hospitalized patient, it can agglutination test, though inexpensive, has an unacceptably low be assumed that the cause is acquired and that the clotting ten- sensitivity and is the one quantitative method that should not be dency will be reversed upon recovery. used. Because some amount of physiologic intravascular clot (e.g., Before therapy is begun, the diagnosis should be verified. The at a wound site) is to be expected in many, if not most, patients at differential diagnosis includes muscle contusion, plantar or gas- risk for DVT, a positive D-dimer assay is of little diagnostic value. trocnemius muscle rupture, ruptured Baker’s cyst, popliteal artery D-dimer assay is therefore unsuitable for screening. In patients sus- aneurysm, arthritis of the knee or the ankle, cellulitis, and myosi- pected of having DVT or PE, however, a negative D-dimer assay tis.The gold standard for diagnosis of DVT is ascending venogra- can, for the most part, rule out DVT and, by extension, PE.32-34 phy. However, study of the entire lower-extremity venous system Various forms of plethysmography (e.g., impedance plethys- mography) have been used to identify nonocclusive DVT.35,36 These techniques are accurate only when there is at least 50% obstruction of the lumen of a deep vein.The presence of large col- Nonocclusive DVT is suspected lateral vessels may result in a false-negative test result as well. Doppler ultrasonography can be performed quickly and easily, Patient may be asymptomatic, or there may be nonspecific though interpretation of the results requires considerable experi- extremity swelling. PE is a common signal. Consider major ence. It has essentially the same drawbacks as plethysmography.35 risk factors, and attempt to determine cause. Real-time B-mode (duplex) ultrasonography can be valuable in this setting.35,37,38 It can actually visualize thrombus within a vessel. Inability to obliterate the vein with probe compression is addition- Onset is apparently Patient has identifiable risk factors al evidence of thrombus. Often, experienced users can even differ- spontaneous for DVT entiate between new and old thrombi on the basis of echogenicity. Consider congenital Assume acquired clotting tendency. Duplex ultrasonography is quite sensitive and specific in patients clotting tendency Proceed with workup. with suspected DVT, and its diagnostic qualities can be further [see Figure 9]. enhanced by the addition of color flow imaging. It has in fact become the noninvasive procedure of choice for assessment of clot in the neck and the extremity vessels. Unfortunately, it is less spe- cific proximal to the axilla and the inguinal ligament, where com- Verify diagnosis pression of the vessels is difficult or impossible. Duplex ultra- sonography is particularly valuable for detecting associated condi- Perform D-dimer assay. tions that may confuse the diagnosis (e.g., muscle hematomas or a Baker’s cyst).38 Ultimately, ascending venography is the most accurate method of diagnosing DVT.39,40 If a good contrast study fails to demon- D-dimer assay is negative D-dimer assay is positive strate the presence of clot, DVT is conclusively ruled out. Once nonocclusive DVT is diagnosed, the treatment of choice Follow patient clinically. Perform definitive diagnostic study is initial therapeutic-dose heparin therapy followed by warfarin (e.g., duplex ultrasonography or ascending venography). therapy. If the patient is responsible and reasonably well educated, initial heparin anticoagulation can be done on an outpatient basis with subcutaneous LMWH.41,42 If this approach is not appropri- ate, inpatient therapeutic-dose I.V. heparin anticoagulation is em- ployed. After 3 or 4 days, depending on the response, heparin is Diagnostic study is Diagnostic study is positive negative for DVT for DVT replaced with warfarin. Give therapeutic-dose unfractionated OCCLUSIVE Follow patient clinically. heparin to aPTT of 60–90 sec or Lower Extremity LMWH (enoxaparin, 1 mg/kg, or equivalent). Lower-extremity occlusive DVT [see Figure 4] is usually associ- ated with swelling; however, if good collateral circulation or dupli- Figure 2 Shown is an algorithm for the management of cate veins are present, especially in the thigh, only local inflamma- nonocclusive DVT. tion may be apparent.Typical findings include pain and tenderness
  • 5. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 5 Figure 3 Injection of dye into dorsal foot veins demonstrates occlusion of iliac veins with excellent pelvic collateral circulation. over the involved veins as well as swelling in the distal limb (which inadequate. Lytic therapy combined with heparin anticoagulation may be minimal with the patient supine). The differential diagno- may be superior to heparin anticoagulation alone, leading to better sis is essentially the same as for nonocclusive DVT. In addition, clearance of clot from the valves with improved function and less lower-extremity DVT can be associated with PE: free-floating clot risk of postphlebitic syndrome.43 may occur in conjunction with occlusive clot. If both legs are swollen, the proximal extent of the thrombus is Upper Extremity likely in the vena cava. If one entire leg is swollen, the proximal For all practical purposes, upper-extremity DVT [see Figure 5] extent must be in the iliac veins. If the swelling is limited to the involves only the axillary, the subclavian, or the innominate vein (or lower leg below the knee, the thrombus is probably in the superfi- a combination thereof). Involvement of the superior vena cava is cial femoral vein. If the only manifestations are minimal swelling rare, mainly occurring in chronic conditions (e.g., long-term venous and calf tenderness, the thrombus is probably limited to the sural catheterization). Arm thrombophlebitis is characterized by pain and vein, the gastrocnemius vein, or both. swelling with tenderness over the involved vein. Often, it is relative- If the patient has a history of DVT, is hospitalized, and is at risk ly asymptomatic: because of the excellent collateral circulation in for recurrence, heparin therapy may be started before test results the arm, thrombosis must be extensive to produce marked swelling. are available (provided that there is no contraindication to antico- Spontaneous onset of axillary or subclavian vein thrombosis can agulation). If the patient is an outpatient, is hospitalized but lacks occur in association with thoracic compression syndromes (effort risk factors for DVT, or has a contraindication to anticoagulation, thrombosis) or as a complication of so-called Saturday night palsy, a D-dimer assay should be performed. If the assay is negative, an in which an alcoholic sleeps with the axilla compressed by the arm alternative diagnosis should be sought. If it is positive, the diag- of a chair. If a potential mechanical cause is not apparent, other nostic workup of DVT should proceed. If diagnostic studies yield possible causes must be explored. The onset of swelling, tender- equivocal results and venography is difficult or impossible, treat- ness, or fever in a patient with a central venous catheter is an indi- ment should proceed as if the diagnosis had been confirmed. cation for removal of the catheter. If there is no bacteremia or fever, The treatment of choice is immobilization in bed, elevation of if there has been a catheter in the vein, and if the problem devel- the limb (with or without elastic compression), and therapeutic- oped spontaneously, sterile thrombophlebitis may be assumed. dose heparin (unfractionated heparin or LMWH), followed by 3 In these cases, once the catheter is removed, anticoagulation is to 6 months of warfarin therapy. If the episode is mild, recovery is unnecessary.44 usually prompt. If pain and swelling do not respond promptly to Subclinical nonocclusive clot is probably of little significance anticoagulation, either the diagnosis is wrong or anticoagulation is because documented PE from the upper extremity is quite rare.
  • 6. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 6 Noninvasive tests [see Nonocclusive, above] typically yield positive Signs of lower-extremity occlusive DVT or PE are present results when the upper extremity is involved.39 Moreover, distal vein catheterization is easy, and phlebography is relatively uncom- Determine whether condition is immediately threatening to plicated.These techniques should be used whenever the diagnosis life or limb. is in doubt. The morbidity of occlusive upper-extremity DVT can be sub- stantial. Thus, if the patient presents with massive swelling of the Condition is immediately Condition is not immediately upper limb, therapeutic-dose heparin anticoagulation should be life- or limb-threatening life- or limb-threatening initiated immediately, and consideration should be given to lytic therapy.43 If phlebography shows compression of arm veins at the Treat as for phlegmasia Perform D-dimer assay. cerulea dolens [see Figure 5]. thoracic inlet after lytic therapy or spontaneous recovery from the thrombotic process, resection of rib 1 may be indicated, particu- larly if positional morbidity is present.45,46 Septic DVT is more common in the upper extremity than in the D-dimer assay is negative D-dimer assay is positive lower, primarily because upper-extremity veins are more frequent- ly catheterized and more often used for injection of illicit drugs. If Follow patient clinically. Perform definitive diagnostic study phlebitis occurs in a catheterized vein with fever and sepsis, the to confirm DVT or PE. catheter should be removed immediately, the tip cultured, and DVT: duplex ultrasonography or Gram staining done on any clot present. Broad-spectrum antibi- ascending venography. otics should be administered until more specific antibiotic therapy PE: pulmonary angiography. can be instituted. Heparin anticoagulation is the primary treat- ment unless contraindicated. Ligation and drainage are not as practical for deep veins as for Diagnostic study is Diagnostic study is positive superficial veins, but either may be indicated on rare occasions if negative for DVT or PE for DVT of PE the process does not respond to conventional therapy within 3 or 4 days and marked swelling and fever persist. Drainage is done on Follow patient clinically. Give therapeutic-dose unfractionated the most accessible portion of the phlebitic process. For ligation, heparin to aPTT of 60–90 sec or the proximal end of the process should be identified via surgery or LMWH (enoxaparin, 1 mg/kg, or phlebography and the vein then ligated proximally. equivalent). MASSIVE (PHLEGMASIA CERULEA DOLENS) Follow with 3–6 mo of warfarin therapy. Phlegmasia cerulea dolens [see Figure 6] is most apt to occur in Figure 4 Shown is an algorithm for the management of lower- dehydrated, cachectic patients and is usually superimposed on extremity occlusive DVT. another critical illness. It can involve either the upper or the lower extremity but more commonly affects the lower. In the lower Signs of upper-extremity occlusive DVT are present (some patients are relatively asymptomatic) Look for signs of septic state. Patient has no signs of Patient has signs of systemic infection systemic infection Assume septic DVT. Perform D-dimer assay. Remove any foreign body; obtain culture and Gram stain as appropriate. Give broad-spectrum antibiotics; give more specific agent once organism is identified. Perform definitive diagnostic study (duplex D-dimer assay is negative D-dimer assay is positive ultrasonography or ascending venography). Follow patient clinically. Perform definitive diagnostic study (duplex ultrasonography or ascending venography). Diagnostic study is Diagnostic study is positive negative for DVT for DVT Figure 5 Shown is an algorithm for the management of upper- Give therapeutic-dose heparin. Treat systemic infection. extremity occlusive DVT. If phlebitis persists, consider ligation or drainage of vein.
  • 7. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 7 and cardiac irritability (with frequent premature beats or tachy- Signs of phlegmasia cerulea dolens are present arrhythmias).54-56 These changes may resolve in moments, and the patient may then appear perfectly normal. In these circumstances, Limb is massively swollen, bluish, and mottled distally. Gangrene is noted. Acute fluid loss and hypovolemic shock are common. the embolus probably either is small or is composed of relatively fresh clot that produces only transient obstruction when it enters the pulmonary vascular tree. Treat phlegmasia cerulea dolens It was long believed that after operation, hospitalization, or injury, the earliest PE might occur was 4 to 7 days after the insult. Replace fluids with isotonic saline, and elevate limb. Start therapeutic- A 1997 study of previously healthy trauma patients, however, dose heparin, and arrange for lytic therapy. found that approximately 25% of the PE episodes occurred in the first 4 days after injury.57 Accordingly, the presence of clinical signs and symptoms consistent with PE in a patient with risk factors calls for appropriate workup, regardless of how soon after the insult Phlegmasia resolves Phlegmasia persists they appear. The differential diagnosis includes acute respiratory distress syn- Consider thrombectomy. drome (ARDS), aspiration, atelectasis, heart failure, pneumonia, and systemic infection. If the diagnosis is not obvious but the risk Figure 6 Shown is an algorithm for the management of massive of PE is substantial and there is no contraindication to anticoagu- DVT (phlegmasia cerulea dolens). lation, heparin therapy (therapeutic-dose unfractionated heparin or LMWH) may be instituted while diagnostic tests are being select- ed and performed. extremity, there is usually simultaneous thrombosis of the iliac, If PE is unlikely, the risk from anticoagulation is high, or other femoral, common femoral, and superficial femoral veins.The limb serious diagnostic possibilities cannot be ruled out, specific studies is massively swollen, bluish, and mottled. Eventually, it becomes (e.g., intravascular coagulation, spiral computed tomography, or nonviable as arterial flow stops because of arterial spasm associat- pulmonary angiography) should be ordered before anticoagulation. ed with venous outflow obstruction.The problem is compounded In a stable patient with suspected PE, a blood D-dimer level by acute massive fluid loss into the limb, which can result in hypo- should be obtained. If the result is negative, PE can be excluded volemic shock. and further diagnostic studies canceled. As with DVT, a positive Treatment involves rapid and aggressive fluid replacement, ele- vation of the limb, and aggressive heparin anticoagulation or catheter-directed lytic therapy.47,48 If the patient does not respond, Table 2—Clinical Features of Pulmonary thrombectomy may be considered, provided that the associated Embolism: Differential Diagnosis disease does not carry a fatal prognosis.49 The procedure is best done transfemorally with a limited incision so that anticoagulation Clinical Feature Other Conditions Associated with Feature can be continued postoperatively. If anticoagulation cannot be continued, thrombophlebitis will recur immediately. Aspiration Atelectasis Pneumonia Pulmonary Embolism Dyspnea Pneumothorax It is widely agreed that PE is grossly underdiagnosed.3,4,50,51 Pulmonary edema Most episodes (up to 90%) are unsuspected,52,53 and only a minor- Systemic infection ity (10% to 25%) of fatal episodes are diagnosed before death. Clin- ical manifestations include dyspnea, hemoptysis, pleurisy, heart Cardiac tamponade failure, and cardiovascular collapse; however, each of these is also Intracardiac injury Heart failure associated with other conditions [see Table 2]. Risk factors for PE are Myocardial contusion similar to those for DVT [see Table 1]. Myocardial infarction PE should be distinguished from pulmonary infarction. Of the Bronchial injury approximately 10% of all pulmonary emboli that are recognized Pulmonary contusion clinically, only 10% are associated with pulmonary infarction.8 Hemoptysis Tracheal erosion Because the lung has excellent collateral circulation, obstruction of Unsuspected neoplasm the larger pulmonary arteries rarely leads to death of lung tissue. When pulmonary infarction does occur, the diagnosis is usually Chest wall injury obvious; hemoptysis, pleuritic chest pain, and a wedge-shaped Pneumonia Pleurisy density on chest x-ray are the classic manifestations. In most PE Pneumothorax patients (i.e., those without pulmonary infarction), these findings Subphrenic inflammation are absent, and the chest x-ray may even be normal. Air embolism For the purposes of clinical diagnosis and treatment, PE is best Cardiac tamponade classified as minor (or suspected), moderate, or catastrophic [see Hypovolemia Figure 7]. Cardiovascular Myocardial infarction collapse MINOR Severe hypoxemia Systemic infection Manifestations of minor PE [see Figure 7a] may include tran- Tension pneumothorax sient tachypnea (with perhaps a slight change in blood gas values)
  • 8. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 8 b a Signs of minor PE (transient Signs of moderate PE (transient hypotension, tachypnea, slight change in blood tachycardia or other arrhythmias, tachypnea, gases, premature beats, ↓ PO2 and PCO2, apprehension, symptoms tachyarrhythmia) are present and signs of pulmonary infarction) are present Perform D-dimer assay. Patient is judged to be at PE is unlikely, or substantial risk anticoagulation seems risky If there is no contraindication to Perform D-dimer assay. D-dimer assay is negative D-dimer assay is positive anticoagulation, give therapeutic- dose heparin while diagnostic tests Seek alternative explanation Assess risk of anticoagulation and are selected. (Alternatively, assume for signs. likelihood of PE. diagnosis and continue treatment as long as risk is present.) PE is likely PE is unlikely, or D-dimer assay is negative D-dimer assay is positive anticoagulation seems risky Give therapeutic-dose No treatment is indicated, except Confirm results with pulmonary heparin. Attempt to make specific for prophylaxis in high-risk patients. angiography. Consider lytic therapy diagnosis via pulmonary Initiate (or continue) therapeutic- for acute episodes. angiography. dose heparin. Figure 7 Shown are algorithms for the management of (a) minor, (b) moderate, and (c) catastrophic PE. Diagnosis is not confirmed Diagnosis is confirmed D-dimer assay does not confirm DVT or PE.The negative predic- If patient is at risk for embolism If anticoagulation is not tive value of the assay for DVT and PE is between 90% and 100% and anticoagulation is not contraindicated, give when an appropriate assay with an appropriate cutoff value is contraindicated, give therapeutic-dose heparin. used.31-33 If a patient is experiencing a life-threatening respiratory prophylactic-dose heparin. If it is, consider vena caval event consistent with PE, the D-dimer assay should be skipped, interruption. therapy instituted, and formal diagnostic studies performed. Noninvasive evaluation of the legs may establish the presence of DVT necessitating anticoagulation. This circuitous way of estab- c lishing the diagnosis of PE has severe limitations. When noninva- Signs of catastrophic PE (cardiac arrest, circulatory collapse, sive assessment aimed at detecting clot in the major leg veins is bradyarrhythmia, severe hypotension, left heart failure) done before documented PE, it yields positive results in only 33% are present to 45% of cases.58 Venography is more sensitive than duplex ultra- Give 100% O2 by ET tube. Give cardiotonic agents and massive sonography. When it is used to diagnose venous thrombosis, as doses of heparin. Consider Trendelenburg’s procedure or many as 30% to 40% of patients with PE are found not to have clot cardiopulmonary bypass. in the major veins of the leg or the abdomen. If the duplex scan or venogram is positive for DVT and there are no contraindications, anticoagulation may be begun. If, on the other hand, a patient is Provide further treatment as needed suspected of having PE but is sent for a duplex scan in place of a pulmonary arteriogram, and the duplex scan is negative, workup If patient survives emergency treatment and improves, continue therapeutic-dose heparin and consider lytic therapy or a caval filter. must continue. It is unacceptable in such cases to assume that the negative result excludes PE. The initial enthusiasm for the use of lung scans to diagnose or screen for PE has diminished.59,60 Current thinking about the use from CT scanning for PE were quite promising.61 of scans for this purpose may be summarized as follows. If a scan In the past few years, CT has undergone rapid increases in is read as high probability, there is roughly an 85% chance that the sophistication. Specifically, as CT technology has moved from sin- diagnosis is correct. If a scan is read as normal, there is roughly a gle-detector to multiple-detector (light-speed) scanners, the sensi- 5% chance that the patient had PE. If a scan is read as low or inter- tivity achievable with this modality has skyrocketed. As a result, mediate probability (the most likely scenario), the likelihood that the negative predictive value of CT in this setting—that is, the the diagnosis is correct is little better than random chance. degree to which a negative CT pulmonary angiogram can be relied As a result of the dramatic improvements in CT imaging, many on to rule out PE—has risen dramatically.62 For most institutions, proposed replacing pulmonary angiography with CT. There were the result of this technologic improvement is that CT angiography several good arguments for this proposal. First, CT scanning is is now the primary radiologic diagnostic study for excluding PE. It less invasive than pulmonary angiography. Second, it does not has been argued that CT angiography cannot yet replace pul- require the immediate presence of a radiologist. Third, it is less monary angiography altogether, because thrombolytic therapy (if costly at most institutions. Finally, CT scanning is usually more required) may be provided during pulmonary angiography, where- easily obtained than pulmonary angiography. The initial results as it typically cannot be provided during CT angiography. This
  • 9. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 9 MODERATE argument probably applies only to the sickest PE patients, who are the ones most likely to benefit from thrombolytic therapy and least Manifestations of moderate PE [see Figure 7b] include transient likely to be able to tolerate a second load of dye (as when pul- hypotension, tachycardia or other cardiac dysrhythmias, tachypnea monary angiography is done for treatment purposes after CT with a significant fall in arterial oxygen and carbon dioxide ten- angiography). sion, apprehension, and symptoms or signs of pulmonary infarc- For critically ill patients, who tolerate diagnostic testing poorly, tion54,56; there may be signs of right heart failure as well. Electro- pulmonary angiography is a more appropriate initial study [see cardiography is rarely helpful in the differential diagnosis. Acute Figure 8].3,50,63 If the angiogram is obtained immediately after the right axis deviation, new incomplete right bundle branch block, clinical episode, particularly if the patient is still symptomatic, a and changes in S1, Q3, or T3 are thought to characterize this disor- negative result rules out PE. However, if the patient improves or der but are found in only a small percentage of patients with recovers before angiography, the angiogram may be falsely nega- proven PE. tive, implying that the clot was minimal or was disposed of by nat- If the diagnosis is probable and there are no likely alternatives, ural lytic processes. Thus, a negative angiogram in such a patient heparin therapy should be initiated. Lytic therapy is of debatable does not unequivocally rule out PE.64 The pulmonary angiogram utility in these patients: compared with standard heparin therapy, does, however, establish the degree of patency of the pulmonary it appears not to reduce mortality or pulmonary dysfunction sig- vasculature, which affects prognosis. nificantly, yet it carries a higher risk of bleeding.3,66 Moreover, lytic PE can occur even immediately after injury in previously healthy therapy is often contraindicated because of recent surgery, injury, persons.57 These early emboli are generated from fresh clot and or vascular punctures. thus are more easily fragmented and broken down.They are much If there is a relative contraindication to anticoagulation (e.g., an more likely to be found in the periphery.65 For these reasons, CT acute surgical wound, a previous bleeding episode, or an allergic is less sensitive in detecting them.65 Accordingly, patients with sus- reaction to heparin) or alternative diagnoses are likely, specific pected PE shortly after injury or operation should undergo pul- diagnosis is required, ideally via pulmonary angiography. Periph- monary arteriography. eral noninvasive venous studies may be helpful because if they If all diagnostic tests for PE yield negative results, therapeutic show significant venous obstruction, the likelihood of PE increas- anticoagulation is not indicated; however, if risk factors are pres- es and the need for therapy is documented. Ventilation-perfusion ent, prophylaxis is indicated. If test results are suggestive or in- scanning, again, is valuable only if strongly positive. dicative of PE, therapeutic heparin anticoagulation should be If there is no contraindication to heparin therapy and the diag- continued. nosis is strongly suspected but not confirmed, therapeutic-dose heparin anticoagulation should be started.67,68 Treatment is con- tinued if the diagnosis is verified and stopped if the diagnosis is excluded.69-72 Vena Caval Filters Vena caval interruption has often been recommended for pa- tients with documented PE despite apparently adequate systemic anticoagulation, but many authorities now advocate vena caval fil- ter placement even in patients who do not have documented thromboembolism but are at high risk and in whom anticoagula- tion is contraindicated.73-75 Supporting data come largely from studies with historical controls. In the one prospective, random- ized, controlled trial involving patients with thromboembolic dis- ease, there was no reduction in mortality at any time, nor was there even a reduction in PE at 2 years; however, there was an increased incidence in DVT over that period.29 These findings suggest that vena cava filters should be reserved for patients with documented DVT, a contraindication to anticoagulation, and a high risk of sub- sequent PE. In 2005, an 8-year follow-up analysis of the patients enrolled in the aforementioned prospective, randomized trial29 was pub- lished.76 Over the 8-year period, the incidence of PE was lower in the group that received inferior vena cava filters than in the group that did not; however, there was an increased rate of recurrent DVT in the filter group. Overall, there was no significant difference in mortality between the two groups. The authors reiterated their recommendation that vena cava filters be used with restraint. If vena caval interruption is considered necessary, it should be done percutaneously via either the jugular or the femoral route. If it is done by the latter route, phlebography (from the insertion site through the vena cava) should be performed first to document the absence of clot along the planned route. A number of different vena caval filters are currently on the market. Each is slightly dif- Figure 8 Pulmonary angiogram shows unequivocal filling defects ferent from the others, but none has demonstrated clear superior- in multiple arteries. ity in preventing PE or reducing caval thrombosis. Surgeons
  • 10. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 10 should be aware of the advantages and disadvantages of the types thrombin stores are depleted, progressively higher heparin doses available at their institutions. will be required to achieve the same degree of anticoagulation. Removable filters are now widely available. Several have been Unfractionated heparin therapy is also frequently referred to as approved by the FDA and are in clinical use. Because these devices conventional anticoagulation.78-80 Before therapy is begun, a clot- were approved comparatively recently, data on long-term efficacy ting battery should be performed, consisting of the aPTT, the and complication rates are not yet available. INR, the platelet count, and levels of fibrinogen, antithrombin, and One of the most critical questions that remains unanswered is, D-dimer. High fibrinogen levels and platelet counts are seen in what will be the long-term consequences when the damage caused patients with chronic clotting syndromes,81 probably representing by the venotomy required for filter removal is superimposed on the overcompensation for increased utilization. Elevated D-dimer lev- endothelial damage caused by the filter? This question should be els suggest intravascular clotting with activation of the fibrinolytic kept in mind, as should the reservations expressed by the authors system. of the only prospective, randomized trial of inferior vena caval fil- In the average patient, therapeutic-dose heparin anticoagulation ters published to date.29,76 Still, it appears that removable vena begins with administration of 5,000 to 10,000 units, followed by caval filters are likely to have a role to play in this setting. They continuous I.V. infusion at a rate sufficient to double or triple the should be considered in patients who are at extremely high risk for aPTT—typically, 1,000 to 2,000 units/hr. When dosages higher PE, who have an absolute contraindication to anticoagulation for a than 2,000 units/hr are required, antithrombin depletion is highly finite period, and in whom anticoagulation can be instituted upon probable. removal of the filter. Tight control of the aPTT change as a result of heparin thera- py is not as important as monitoring for evidence of bleeding and CATASTROPHIC platelet depletion. Clinical evidence of bleeding is not necessarily a Catastrophic PE [see Figure 7c] is most apt to be superimposed contraindication to anticoagulation. Minimal amounts of blood on a critical illness or a major operation.The peak incidence is 7 to may be lost in the urine or through the GI tract; if the patient has 10 days after the procedure or the onset of clinical illness, though a clearly identifiable need for anticoagulation, such minor blood emboli may occur at any time.54 The reason for this apparent delay loss should be accepted. Only when transfusion is indicated to is that for the clot to remain intact after embolization to the pul- maintain the hematocrit should discontinuance of heparin be con- monary vasculature, it must mature in the vascular system, a sidered. At that point, if the risks of bleeding seem to outweigh the process that takes several days. Fresh clot breaks up readily and benefits of anticoagulation, heparin infusion can be stopped or dissipates promptly, whereas older clot is resistant to lysis. The reduced to prophylactic levels. It is important to watch for falls in manifestation of early embolization of fresh clot to the pulmonary the hematocrit indicative of significant bleeding. The most com- vasculature is ARDS. Embolization of older clot can produce acute mon sites for hemorrhagic complications are surgical wounds and pulmonary obstruction and acute right heart failure, making radi- the retroperitoneum. Retroperitoneal bleeding is generally asymp- ologic diagnosis of PE relatively easy.54 Occlusion of large portions tomatic until the patient progresses to hemorrhagic hypovolemic of the vasculature is associated with hemodynamic catastrophe. shock. Typically, the clinical onset of catastrophic PE comes when a As a rule, the therapeutic dose of LMWH is twice the prophy- patient, having just been mobilized, performs a vigorous Valsalva lactic dose.The various LMWHs currently on the market all have maneuver in the course of his or her first postoperative bowel slightly different activities and half-lives. Enoxaparin may be taken movement. The great abdominal veins distend, and any clot pres- as prototypical. The accepted prophylactic dose for enoxaparin is ent tends to be stripped loose. If a large clot embolizes, immediate 30 mg twice daily, and the therapeutic dose is 60 mg (or 1 mg/kg) collapse and cardiac arrest may result; in some cases, brady- twice daily. arrhythmia or severe hypotension precedes the actual arrest. A major benefit of using LMWHs to treat DVT and PE is that Immediate emergency treatment comprises intubation and admin- therapeutic doses can be given subcutaneously.41,42 As a result, istration of 100% oxygen, heparin anticoagulation, and, if cardiac patients may be treated as outpatients both in the acute phase of arrest occurs, cardiopulmonary resuscitation. A Swan-Ganz cath- the disease and in the subacute phase, during the transition to oral eter should be inserted as soon as possible so that the effects of anticoagulants. This approach requires that patients be clinically therapy can be monitored. Cardiotonic agents (e.g., dopamine, 2.0 stable and able to follow dosing instructions. Because there are no to 5.0 µg/min, or dobutamine, 2.5 to 10.0 µg/kg/min) should be validated methods of monitoring LMWH therapy, an initial assess- administered to strengthen myocardial function. If sudden arrest ment of antithrombin activity is appropriate. If this is low, unfrac- occurs in circumstances that permit emergency thoracotomy, tionated heparin therapy in conjunction with aPTT monitoring is Trendelenburg’s procedure can be performed; however, it is rarely probably preferable. indicated and even more rarely successful. If the patient survives initial emergency treatment and improves, high-dose heparin ther- High Dose apy should be continued and lytic therapy considered.71,77 High-dose heparin therapy is reserved for patients who are dying of PE or are at risk for immediate limb loss from phlegma- sia cerulea dolens. Such therapy consists of administering a large General Principles of Anticoagulation and Lytic Therapy enough dose of heparin to elevate the aPTT off the scale.The max- imum aPTT that can be measured by our laboratory is 150 sec- HEPARIN ANTICOAGULATION onds; high-dose heparin treatment should therefore yield an aPTT higher than this value. Theoretically, given that a fully anticoagu- Therapeutic Dose lated patient should not form clot at all, the aPTT should be infi- Heparin therapy may be instituted with either unfractionated nite.This method of treatment may be used in patients with imme- heparin or LMWH. In either case, the key is to give enough heparin diately life-threatening PE or phlegmasia cerulea dolens when the soon enough to have a beneficial effect. Both types of heparin exert more conventional technique, catheter-directed thrombolytic ther- their effect by potentiating antithrombin; thus, if a patient’s anti- apy, is unavailable.
  • 11. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 11 In most patients, high-dose therapy begins with a 20,000 unit anticoagulant must be used. The most widely accepted agent for I.V. bolus, followed by infusion of 5,000 units/hr I.V.82-86 The end this purpose is lepirudin (a direct thrombin inhibitor).92 Other point of therapy is clinical evidence of improvement. In patients direct thrombin inhibitors (e.g., argatroban) and heparinoids (e.g., being treated for PE, pulmonary function should improve. danaproid) have also been successfully used to provide anticoagu- Because complete anticoagulation is the essential principle of lation in patients with HIT. None of the LMWHs are acceptable high-dose heparin therapy, there is no need to be concerned about in this setting, and at present, the FDA does not allow use of the an upper limit for the dosage: if the patient cannot clot, doubling pentasaccharide in severe HIT. or even tripling the dosage should not increase the risk of bleed- Unlike warfarin, heparin does not cross the placenta and has not ing. Moreover, because the incidence of bleeding is very low in the been associated with fetal malformations; thus, it is preferred for first 2 or 3 days of therapy, regardless of the dosage,85,86 high ini- thrombotic complications of pregnancy. Heparin can be adminis- tial dosages do not carry an unacceptable bleeding risk. After tered subcutaneously in an outpatient setting for 3 to 6 months. heparin has been observed to have an effect and a prolonged Long-term administration can lead to osteoporosis and sponta- aPTT documented, the high dosage should be continued for at neous vertebral fractures.93 least 24 hours, then decreased by 500 to 1,000 units/hr over the Very rarely, heparin therapy can lead to adrenal hemorrhage next 24 hours. If the clinical effect is maintained and improvement and consequent adrenal insufficiency.79 If acute adrenal insuffi- continues, the dosage can be decreased by another 500 to 1,000 ciency is suspected, anticoagulant therapy should be discontinued units/hr over the following 24 hours. In theory, once all clotting and high-dose steroid therapy (preferably with hydrocortisone) stops, natural antithrombin levels should recover, allowing lower initiated.Treatment should not await laboratory confirmation. CT dosages of heparin to be effective. After 3 or 4 days of therapy, the scanning may be useful. Heparin may suppress aldosterone syn- dosage may be reduced to more conventional levels [see Thera- thesis, especially with prolonged use.79 peutic Dose, above]. If the initial improvement is lost, the dosage should be restored Reversal of Heparin Effect to its previous high level and maintained there for several days The anticoagulant effect of heparin disappears within hours before any attempt is made to reduce it again. The platelet count after discontinuance. If the effect must be reversed quickly, the and the hematocrit should be carefully monitored, the latter at patient should receive protamine sulfate I.V. This agent binds the least four times a day. Heparin should be discontinued or the heparin and prevents it from activating antithrombin. Protamine dosage reduced only when the risks of bleeding and transfusion sulfate should be given in the smallest dosages that still evoke the exceed the benefits of anticoagulation. In a monitored environ- desired result—typically, about 1 mg for every 100 units of heparin ment, patients very rarely die of hemorrhage; rather, they die of the remaining in the patient. It should be administered slowly over 5 consequences of clotting. to 10 minutes; rapid infusion can cause shortness of breath, flush- ing, bradycardia, hypotension, or anaphylaxis. On rare occasions, Complications patients previously sensitized to protamine may experience mas- The most devastating hemorrhagic risk of heparin therapy— sive platelet aggregation, as manifested by catastrophic arterial fortunately, a rare one—is intracranial bleeding. The risk of major thrombosis. Patients particularly likely to manifest this adverse hemorrhage ranges from 4% to 9% and is directly affected by how reaction include diabetics and persons with fish allergies. Prota- tightly the INR is controlled.87 The risk is greatest in elderly mine has little or no capacity for reversing either LMWH or fonda- patients, particularly women,79 but it is still small in comparison parinux. Research aimed at developing specific protamines to with the obvious risks posed by the clotting episode. Nevertheless, inactivate the LMWHs is now being carried out, but at present, no the existence of this risk makes it appropriate to use high-dose such agents are available in the United States. heparin primarily in life-threatening conditions. ORAL ANTICOAGULATION A more common complication of full heparin anticoagulation is retroperitoneal bleeding. This problem is accentuated in elderly Warfarin is the prototypical oral anticoagulant; the agents in this patients. Because aging is associated with loss of connective tis- class have much the same effects, differing primarily with respect sue elasticity, bleeding into retroperitoneal connective tissue that to potency and duration of action.79,80 Warfarin is also available in would normally be insignificant can become life-threatening. an I.V. form; however, in view of its mechanism of action, caution Usually, this is not a serious problem if the hematocrit is followed, should be exercised when it is given parenterally. heparin dosing adjusted, and lost blood replaced. When the per- ceived risk of bleeding outweighs the thrombotic risk, heparin Dosage should be discontinued. Historically, warfarin dosage has been regulated by monitoring Two forms of acute heparin-induced thrombocytopenia (HIT) the prothrombin time (PT), with a PT 1.5 to 2.5 times normal (11 have been reported.88-91 Mild HIT occurs in 2% to 5% of patients or 12 seconds) generally considered to represent the optimal level. 2 to 15 days after the initiation of therapy.The platelet count usu- In response to the wide variations in PT reported by different lab- ally remains at about 100,000/mm3, and treatment can be contin- oratories, the World Health Organization (WHO) has recom- ued without undue risk of bleeding or thrombosis. Severe HIT is mended substituting the INR for the PT ratio so that all laborato- much less frequent. It usually occurs about 7 to 14 days after the ry assessments will be comparable.94 An INR of 2.0 to 3.0 corre- initiation of heparin therapy and is reversible once the drug is dis- sponds to a PT that is 1.3 to 1.5 times normal (moderate dose); continued. It is not dependent on the heparin dose given. Clinical an INR of 3.0 to 4.5 corresponds to a PT that is 1.5 to 2.0 times manifestations include a substantial (at least 50%) drop in the normal (high dose). Lower INRs are recommended for all but platelet count followed by a thrombotic episode (frequently both extremely high-risk patients (e.g., those with mechanical heart arterial and venous). An ELISA directed at the platelet factor valves) [see Table 3].94 4–heparin complex is generally accepted for laboratory confirma- Initially, the daily dose of warfarin required to increase the INR tion of the diagnosis. Treatment consists of discontinuance of to between 2.0 and 3.0 is estimated and administered.The INR is heparin. If the patient still requires anticoagulation, a different then checked every morning. If it suddenly overshoots the target
  • 12. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 12 elimination of the intestinal flora by antimicrobial agents, may have Table 3—Recommendations for Use of similar effects. For these reasons, warfarin should be used with Varying Dosages of Warfarin great caution in patients who are receiving antibiotics or who can- not tolerate a regular diet. The dosage of warfarin is regulated by monitoring the INR. A less There are some serious interactions that increase the risk of intense therapeutic range (INR = 2.0 to 3.0, corresponding to a PT bleeding without altering the INR. These include inhibition of 1.3 to 1.5 times normal with a WHO-designated thromboplastin) is appropriate for the following applications: platelet function by drugs such as aspirin and gastritis or gastric ulceration induced by anti-inflammatory drugs. Obviously, when 1. The prevention of venous thromboembolism in high-risk patients. placing a patient on more than one anticoagulant simultaneously, 2. The treatment of venous thrombosis and PE after an initial course of heparin. great care must be taken. 3. The prevention of systemic embolism (a) in patients with tissue Complications heart valves, (b) in selected patients with atrial fibrillation, (c) in patients with acute anterior wall myocardial infarction, and (d) in Bleeding is the major complication of oral anticoagulation.Tight patients with valvular heart disease. control of warfarin therapy is essential for minimizing this compli- A more intense therapeutic range (INR = 3.0 to 4.5, corresponding cation.87 Bleeding is rare when the INR is kept below 3.0. When to a PT 1.5 to 2.0 times normal with a WHO-designated thromboplastin) is appropriate for patients with mechanical bleeding does occur, a preexisting lesion is likely. If the bleeding is prosthetic valves and patients with recurrent systemic embolism. minor, the warfarin dosage should be adjusted; if it is major, the INR—international normalized ratio—PT—prothrombin time—WHO—World Health drug may have to be discontinued.The risk of intracerebral or sub- Organization dural hematoma is greater with warfarin than with heparin, partic- ularly in patients older than 50 years. If there is any sign of hem- orrhage, the next anticoagulant dose should be withheld and the range, the warfarin dosage is reduced. If the INR has not reached INR measured. For continued or serious bleeding, 5 to 10 mg of or surpassed 1.5 after the third dose, the dosage is increased. The vitamin K1 oxide (phytonadione) I.V. is effective. Several hours maintenance dosage averages about 5 mg/day but may range from may pass before hemostasis improves significantly, and 24 hours or 1 to 10 mg/day. longer may be needed for maximal effect. If immediate restoration While the maintenance dosage is being determined, the INR of hemostatic competence is necessary, levels of vitamin K–depen- should be checked daily. Once the patient stabilizes, the INR can dent coagulation factors can be raised by giving fresh frozen plas- be checked less often: twice weekly for the first few weeks, once ma, 10 to 20 ml/kg body weight, or prothrombin complex con- weekly for the next several months, and once monthly thereafter if centrate.96 the patient is stable. The patient should be cautioned about drug Administration of warfarin during pregnancy can cause birth interactions. If the dosages of other medications are changed, the defects and abortion and therefore is contraindicated. Warfarin- impact on the INR should be investigated and the warfarin dosage induced skin necrosis is a rare complication of oral anticoagulant adjusted as appropriate. therapy.90 This syndrome, characterized by the appearance of skin lesions shortly after initiation of treatment, may be the result of a Duration There is no general agreement on how long oral anticoagulant therapy should be continued after a thromboembolic event. Table 4—Factors Influencing Current data suggest that the duration of therapy should be based Response to Warfarin on the level of underlying risk rather than on the severity of the event. For patients with a limited risk period (e.g., a young patient with a femur fracture and no other risk factors), an 8- to 12-week Factors Leading to Factors Leading to Increased Response Decreased Response course is as efficacious as a longer course.95 For patients with a life- long risk (e.g., a patient with a congenital hypercoagulability syn- Drugs Drugs drome or cancer), a therapeutic dosage for 3 to 6 months, followed Allopurinol Barbiturates by a low dosage for the remainder of the patient’s life, is indicat- Amiodarone Cholestyramine ed.87 Lengthening the duration of full anticoagulant therapy in Aspirin Diuretics patients with long-term risk factors appears only to delay the recur- Cephalosporins Ethanol (chronic use) rence of thromboembolism, not to prevent it. Cimetidine Phenytoin Clofibrate Rifampin Drug Interactions Disulfiram Vitamin K Response to warfarin is affected not only by various bodily fac- Ethanol (acute intoxication) Foods tors but also by drug interactions [see Table 4]. Such interactions are Heparin Green leafy vegetables most dangerous when drugs administered in parallel are taken Metronidazole Bodily factors intermittently.79,80 Increased metabolic clearance of the drug can Sulfinpyrazone Hereditary resistance result from administration of barbiturates, rifampin, or phenytoin; Trimethoprim-sulfamethoxazole Hypometabolic states long-term use of alcohol; ingestion of large amounts of vitamin K; Bodily factors Pregnancy and rich foods. Elevated levels of coagulation factors during preg- Age Uremia nancy also decrease warfarin’s effectiveness. Congestive heart failure Decreased metabolism or displacement from protein-binding Dietary inadequacy sites caused by phenylbutazone, sulfinpyrazone, metronidazole, Hypermetabolic states disulfiram, allopurinol, cimetidine, amiodarone, or acute intake of Intestinal flora loss ethanol can elevate the INR and increase the risk of hemorrhage. Liver disease Relative vitamin K deficiency, resulting from inadequate diet or the
  • 13. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 13 Table 5 Characteristics of Current Thrombolytic Agents Half-life Fibrin- FDA-Approved Agent Abbreviation Antigenic Comments Current Trials (min) Specific Indication AMI, PE, DVT, PAO, — Streptokinase SK 30 No Yes Systemic plasminogen activator AV cannulae Urokinase UK 15 No No AMI, PE, catheter Systemic plasminogen activator occlusion — GUSTO Alteplase t-PA 4–8 Yes No AMI, acute stroke, PE Sometimes termed accelerated t-PA TIMI Increased fibrin specificity; ASSENT-II Reteplase rt-PA 14–18 Yes No AMI increased resistance to PAI-1 In-Time II Resistance to plasmin cleavage; Tenecteplase TNK-tPA 11–20 Yes No AMI increased effectiveness on ASSENT-II arterial thrombi Anistreplase APSAC 40–70 No AMI Not commonly used, Lys-plasmino- No — gen complex with streptokinase Lanoteplase n-PA No Increased resistance to PAI-1, less 23–37 No — In-TIME II fibrin specificity Recombinant urokinase-type Saruplase rpro-UK 7–9 No No — plasminogen activator without PROACT III immunogenicity Reduction in antigenicity with Staphylokinase SakSTAR Selectively Yes variants, fibrin-bound is not 6 — CAPTORS II rSak inhibited by α2−antiplasmin Pamiteplase YM866 30–47 No No — Resistance to plasmin cleavage — Bat-PA Vampire bat PA; greater fibrin b-PA t12α:1 / Desmoteplase Yes Minimally — specificity than tissue plasmino- DEDAS DSPA t12β:17 / gen activator DSPAα1 Monteplase E6010 23 No Unlikely — — COMA AMI—acute myocardial infarction ASSENT— Assessment of the Safety and Efficacy of a New Thrombolytic Agent AV—arteriovenous CAPTORS—Collaborative Angiographic Patency Trial of Recombinant Staphylokinase COMA—Combining Monteplase with Angioplasty DEDAS—Dose Escalation study of Desmoteplase in Acute Ischemic Stroke DVT—deep vein thrombosis In-TIME—Intravenous n-PA for Treatment of Infarcting Myocardium Early PA—plasminogen activator PAI—plasminogen activator inhibitor PAO—peripheral arterial occlusion PE—pulmonary embolism PROACT—Prolyse in Acute Cerebral Thromboembolism transient hypercoagulable state caused by depletion of the natural tion were randomly assigned to receive either warfarin or ximela- anticoagulants (proteins C and S) before the onset of warfarin’s gatran for stroke prophylaxis.98 The authors found no significant effect. To mitigate the initial hypercoagulable state, some advocate differences in the rates of stroke, embolism, or death but did note starting warfarin therapy only after initial heparinization. a significantly higher incidence of bleeding in the warfarin group. They also found that a significant percentage of the patients in the Investigational Oral Anticoagulant ximelagatran group had increases in their hepatic enzymes that A newer oral anticoagulant, the direct thrombin inhibitor ximela- were correlated with administration of the drug. In addition, there gatran, has been approved for use in Europe and has been widely were cases of fatal hepatic failure that could have been associated studied; however, it has not been approved by the FDA for use in with the drug. the United States. Initial studies of this agent yielded promising Thus, ximelagatran appears to hold great promise, but it is un- results, raising hopes that there might be an effective oral anticoag- clear whether it will be approved for the American market. ulant that is safer and easier to administer than warfarin. LYTIC THERAPY In a prospective, double-blind study from 2003, more than 1,800 patients undergoing knee surgery were randomly assigned to A number of different lytic agents have been studied [see Table 5]. receive either ximelagatran or warfarin.97 Venography was per- At present, however, lytic therapy is generally understood to refer formed on day 7. Warfarin was given in standard dosages, with a to administration of streptokinase, urokinase, or t-PA,79,80,99-102 all of target INR of 2.0 to 3.0. Ximelagatran was given in two different which act on the endogenous fibrinolytic system to convert plas- doses (as a dosing trial), without monitoring. The authors observ- minogen to plasmin. Streptokinase combines with plasminogen to ed a significantly lower incidence of DVT in the ximelagatran form streptokinase-plasminogen complexes that are converted to group, with no significant difference in bleeding. After the publica- streptokinase-plasmin complexes, which then convert residual plas- tion of this study, several reports of adverse reactions (specifically, minogen to plasmin.79,102 Urokinase directly cleaves a peptide bond liver failure) were reported to the FDA. in the plasminogen molecule to form plasmin. t-PA binds to fibrin In a subsequent study, almost 4,000 patients with atrial fibrilla- via lysine binding sites at the N-terminal.
  • 14. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 14 Lytic therapy is most effective when it can be initiated within effects are clinically indistinguishable from those of urokinase. Like hours. It is worth attempting when the clot has been present for less urokinase, t-PA is extremely expensive. than 1 week, particularly if it has been present for less than 3 days. When lytic therapy is begun, heparin therapy usually is temporari- Technique of Administration ly discontinued because of the theoretical possibility of increased The traditional method of administering lytic therapy, venous bleeding risk; it may be resumed immediately upon completion of infusion, is widely used to treat coronary artery thrombosis104; lytic therapy. If, however, the problem is immediately life-threaten- however, it is only modestly effective against peripheral arterial ing (e.g., myocardial infarction or massive PE), anticoagulation occlusion and is associated with a high rate of hemorrhagic com- should probably be done in parallel with lytic therapy to prevent plications.105 Current methods focus more closely on the site of rethrombosis. occlusion, particularly with the development of intra-arterial infu- sion techniques. Indications and Contraindications Lytic therapy for acute PE has attractive theoretical benefits; The indications for lytic therapy are being extended.96 Uro- however, the FDA currently approves this approach only for pa- kinase, t-PA, and, to a much lesser degree, streptokinase are being tients with so-called massive PE (i.e., PE resulting in both shock used for venous thrombotic conditions, such as symptomatic ob- and heart failure). Clinical trials demonstrated that in patients who struction of major upper-extremity veins.The morbidity of axillary were hemodynamically unstable as a result of PE, thrombolysis vein thrombosis can be considerable; clearance of clot may not only achieved greater improvements in intermediate end points (e.g., help restore patency but also help identify the underlying cause. In right ventricular function) than heparin alone did, though survival the lower extremities, more thorough clearance of clot should, in was not improved.106 Subsequent studies evaluated recombinant t- theory, help restore valve function and prevent so-called post- PA in patients with so-called submassive PE, with similar results.66 phlebitic syndrome.101,103 Contraindications to lytic therapy include surgery in the previ- Monitoring ous 10 days, serious GI bleeding in the previous 3 months, a histo- Although monitoring of lytic therapy is less standardized than ry of hypertension, an active bleeding or hemorrhagic disorder, a monitoring of anticoagulant therapy, several principles should be previous cerebrovascular accident, and an active intracranial pro- followed.The effects must be monitored from both a clinical and a cess. As with heparin, the risk of intracranial bleeding is increased laboratory perspective. Clinical monitoring involves following im- in older patients; the risk appears to be higher with t-PA than with provements on the angiograms. Laboratory monitoring has three streptokinase or urokinase. components. First, D-dimer levels should be measured; a marked increase signals that cross-linked fibrin is undergoing breakdown. Agents Second, adequate stores of plasminogen should be documented; Streptokinase Streptokinase is a 47 kd protein produced by without plasminogen, none of the thrombolytic drugs are effective. β-hemolytic streptococci. Because it is not endogenous, circulating Third, fibrinogen levels should be followed to prevent exhaustion of antibodies to it (from previous streptococcal infections) often are native clotting; most authorities recommend that lytic therapy be already present in plasma.When streptokinase is infused, a loading discontinued once fibrinogen levels fall below 50 mg/dl. Previously, dose must be given to overcome these antibodies. Once the anti- the TT was used for monitoring thrombolysis; today, however, bodies are depleted, the half-life of streptokinase is about 80 min- given the recommendation for concurrent use of heparin,104 the TT utes. Achievement of the desired therapeutic effects is confirmed by is considered to be of little value in this setting. documenting a rise in the thrombin time (TT), a fall in the fi- brinogen level, or an abrupt rise in the D-dimer level. Because Complications streptokinase may deplete circulating plasminogen after a few The major toxicity of all three major lytic agents is hemorrhage, hours, the optimal approach may be to administer it for 6 hours by resulting from (1) lysis of physiologic thrombi occurring at vascu- continuous infusion every 24 hours for 2 or 3 days, then to admin- lar injury sites and (2) a systemic lytic state caused by the systemic ister heparin in the intervals between infusions. formation of plasmin. The incidence of bleeding is many times higher after lytic therapy than after anticoagulant therapy and is Urokinase Urokinase is a 34 kd globulin originally found in dependent on both the dosage and the duration of lytic therapy. human urine and now isolated from cultured human cells. It has a Careful administration of lytic agents can keep the incidence of half-life of 15 minutes and is metabolized by the liver. It was major hemorrhage below 5% and the incidence of intracranial removed from the U.S. market for several years as a result of con- hemorrhage below 1%.102 cerns expressed by the FDA, but it subsequently was reintroduced A potential major complication is distal embolism of partially after these concerns were satisfactorily addressed. For catheter lysed clot. In theory, this possibility should rule out lytic therapy for clearance, a solution containing 5,000 units/ml should be infused treating thrombus in the heart or in the cerebrovascular system.102 into the obstructed tubing. Urokinase is not fibrin-specific and Surprisingly, however, dislodgment of intracardiac clot as a result therefore produces a systemic lytic state. Its primary disadvantage of lytic therapy is rare. is that it costs far more than streptokinase. Streptokinase causes several adverse reactions that urokinase and t-PA do not. When first produced, streptokinase was associat- t-PA Tissue plasminogen activator is an enzymatic glycopro- ed with a very high incidence of antigenicity and severe pyrogenic tein composed of 527 amino acids that is produced from a human reactions.The current purified formulation is relatively free of pyro- melanoma cell line by means of recombinant DNA technology. Its gens and has a reduced incidence of allergic side effects, but it is half-life is approximately 4 minutes; it is metabolized by the liver, still antigenic and may still cause allergic reactions or, in rare and approximately 80% of the dose is excreted in the urine within instances, anaphylaxis. Streptokinase may also induce the forma- 18 hours. It is not antigenic and does not promote antibody for- tion of additional antibodies that make re-treatment impossible. In mation. Theoretically, t-PA should be somewhat more specific for contrast, retreatment with urokinase may be carried out as often as fibrin clot than urokinase or streptokinase. In practice, however, its necessary with minimal risk of allergic reactions.
  • 15. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 15 Hypercoagulability States clude inherited thrombophilia, because the defects have a low pen- Certain patients seem to have a tendency to clot spontaneously. etrance, and fresh mutations may have occurred. So-called hypercoagulability states were long thought to exist, but they were difficult to document except on clinical grounds. Cur- INITIAL LABORATORY ASSESSMENT rently, however, these clotting tendencies are better understood,107 Initial evaluation of a patient with an unexplained thrombotic thanks in large part to recognition of the role of antithrombins. If episode should be directed at the most common causes of hyper- an antithrombin deficiency exists and clotting goes unchecked, coagulability. Acquired causes of clotting are more commonly seen activation of a clotting cascade could theoretically progress to clot- by surgeons than congenital causes and therefore must be exclud- ting throughout the entire vasculature. Another important devel- ed first. If a clotting disorder is determined to be congenital, a lab- opment was the recognition that deficiencies of certain natural clot- oratory workup should be undertaken. Several of the relevant removing substances in the blood may lead to a clinical throm- assays (see below)—specifically, the functional assays—should be botic tendency. Both types of deficiency can be either acquired or performed after the acute phase of the disorder has passed. If they congenital. are performed during the acute phase, levels of several antithrom- botics (e.g., antithrombin and proteins C and S) will be mislead- SCREENING ingly low—not because deficiencies of these substances caused the When the etiology of a clotting episode is unclear, the family his- underlying thrombotic process but because they were consumed in tory should be reviewed for evidence of a congenital disorder. Even that process. if the history is negative, the patient should be screened for both acquired and congenital disorders [see Figure 9]. SPECIFIC CAUSES OF THROMBOTIC TENDENCY The most common congenital causes of accelerated clotting are Acquired Clotting Conditions mutations of prothrombin (prothrombin G20210A mutation) and Screening for acquired clotting conditions [see Table 6] is based factor V (Leiden mutation, or activated protein C resistance).114-116 on the history, physical examination, and laboratory assessment. The prevalence of each of these ranges from 1% to 5% in the gen- The history should include medications, diseases, and surgical eral population and may be much higher in specific ethnic sub- procedures or other injuries.108-110 Examination may disclose populations.117 Each mutation may be identified conclusively by causes of hypercoagulability.111 Soft tissue injury, for example, is means of polymerase chain reaction (PCR) techniques. Detection a potent activator of the coagulation system. If the injury is severe of these mutations, unlike assays for antithrombin and proteins C enough, it may be capable of causing a severe acquired coagu- and S, is not dependent on the patient’s current inflammatory lopathy. The problem is usually obvious, but on occasion, de- state. It must be remembered that the presence of one of these tailed study may be necessary to identify tissue damage or ische- mutations, especially in the heterozygous form, does not imply that mic injury to bowel or extremities. Hypovolemia—especially it is the sole cause of thrombosis. In many patients, a second pre- hypovolemic shock—markedly reduces clotting time: blood from cipitating factor must be present for the pathologic genetic throm- a patient in profound shock may clot instantaneously in the botic potential to be manifested. syringe as it is being drawn. The breakdown of red cells in a hemolytic transfusion reaction can cause clotting. Severe infec- Prothrombin G20210A Mutation tion, especially from gram-negative organisms, is a potent activa- The prothrombin G20210A mutation is known to involve a sin- tor of coagulation.112 gle amino acid substitution in the prothrombin gene, but precisely Of the acquired hypercoagulability syndromes, Trousseau syn- how this increases the risk of venous thromboembolism is unclear. drome is a particularly important condition for surgeons to recog- The one apparent manifestation of the mutation is a 15% to 40% nize because it occurs in the surgical population (cancer patients) increase in circulating prothrombin. Regardless of the mechanism and must be treated with heparin (it is unresponsive to warfarin). at work, patients who are at least heterozygous for the trait are at It occurs when an adenocarcinoma secretes a protein recognized two- to sixfold greater risk for venous thromboembolism than those by the body as tissue factor, resulting in multiple episodes of ve- without the mutation.118 nous thromboembolism over time (migratory thrombophlebitis). Simple depletion of vitamin K–dependent factors is ineffective. Resistance to Activated Protein C (Factor V Leiden) Patients should receive therapeutic-dose heparin indefinitely or Resistance of human clotting factors to inactivation by activated until the cancer is brought into remission.113 protein C is believed to be the most common inherited procoagu- Laboratory screening may facilitate diagnosis. A complete blood lant disorder.114 Normally, activated factor V is degraded by acti- count may document the presence of polycythemia or leukemia. vated protein C in the presence of membrane surface as part of Thrombocythemia may be a manifestation of a hypercoagulable normal regulation of thrombosis. Activated protein C resistance is disorder, and thrombocytopenia after the administration of caused by a single substitution mutation in the factor V gene, which heparin raises the possibility of intravascular platelet aggregation. is passed in an autosomal dominant fashion. The mutant factor V A prolonged aPTT is suggestive of lupuslike anticoagulant. that results, termed factor V Leiden, is resistant to inactivation by Increased levels of D-dimers, fibrin degradation products (FDPs), activated protein C and thus has a greater ability to activate throm- or fibrin monomers in the plasma may reflect low-grade intravas- bin and accelerate clotting. cular coagulation. Two techniques are commonly used to diagnose this disorder. The first is a functional assay that compares a standard aPTT to one Congenital Clotting Conditions performed in the presence of exogenous activated protein C. If the Congenital clotting tendencies can result from deficiencies in latter aPTT does not exhibit significant prolongation, the patient is inhibitors of thrombosis (antithrombin, proteins C and S, and pos- probably resistant to activated protein C. The results of this assay sibly heparin cofactor II), dysfibrinogenemias, or dysfibrinolysis must be interpreted with caution if the patient is still in the acute [see Table 7]. Most congenital clotting defects are transmitted as an phase of the illness. The second technique, which is more reliable, autosomal dominant trait. A negative family history does not pre- involves direct detection of the mutation via PCR analysis of DNA.
  • 16. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 16 Etiology of clotting episode is unclear Review family history for evidence of congenital disorder. Family history is negative Family history is positive Screen for acquired thrombotic syndromes. • History: Focus on medications, diseases, and injuries (surgical and other). • Physical exam: Seek evidence of tissue injury or necrosis, shock, transfusion reactions, or infection. • Laboratory assessment: Order appropriate tests—CBC, platelet count, aPTT, D-dimer, FDPs, fibrin monomer. Screening is positive Screening is negative Treat acquired disorders if possible. Work up patient for most common thrombophilias: prothrombin 620210A mutation and Leiden mutation (activated protein C resistance). Screening is positive for prothrombin Screening is negative for prothrombin 620210A mutation or Leiden mutation 620210A mutation and Leiden mutation Give therapeutic-dose heparin. Assess thrombin time, euglobulin clot lysis, and antithrombotic activity. Thrombin time is prolonged Euglobulin clot lysis time is Thrombin time and euglobulin prolonged clot lysis time are normal Suspect dysfibrinogenemia. Perform reptilase test and specific functional Suspect dysfibrinolysis. Apply Suspect antithrombin deficiency. assays for fibrinogen. tourniquet to verify fibrinolytic Perform specific assays for defect. Perform specific assays for antithrombin, proteins C and S, plasminogen, t-PA, and t-PA inhibitor. and heparin cofactor II. Initiate appropriate therapy • Dysfibrinogenemia: Give therapeutic-dose heparin followed by long-term warfarin. • Dysfibrinolysis: Essentially the same as for dysfibrinogenemia. • Antithrombin deficiency: Give sufficient heparin to raise aPTT slightly, followed by long-term warfarin. If anticoagulation is contraindicated, give FFP containing antithrombin. • Protein C or S deficiency: Give FFP, factor IX concentrate, or therapeutic-dose heparin followed by warfarin. • Heparin cofactor II deficiency: Essentially the same as for antithrombin deficiency. Figure 9 Shown is an algorithm for screening for acquired and congenital thrombotic syndromes. Antithrombin Deficiency and 1,000-fold by administration of exogenous heparin. Antithrombin (once termed antithrombin III) is a 65 kd pro- Congenital antithrombin deficiency occurs in approximately tein that decelerates the coagulation system by inactivating acti- 0.01% to 0.05% of the general population and 2% to 4% of vated factors—primarily factor Xa and thrombin but also fac- patients with venous thrombosis.119 The trait is passed on as an tors XII, XI, and IX.119,120 Antithrombin therefore acts as a autosomal dominant trait, with the heterozygous genotype being scavenger of activated clotting factors. Its activity is enhanced incompatible with life. Antithrombin-deficient patients are at in- 100-fold by the presence of heparans on the endothelial surface creased risk for thromboembolism when their antithrombin activ-
  • 17. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 17 which protein C antigen levels are normal but protein C activity is Table 6—Etiology of Acquired low, and these would not be detected by the usual immunoassays. Hypercoagulability Protein S is a vitamin K–dependent protein that acts as a cofac- tor for activated protein C by enhancing protein C–induced inac- Tissue and cellular damage Disease tivation of activated factor V.The incidence of protein S deficiency Shock Blood dyscrasias is similar to that of protein C deficiency.123 It is transmitted as a Trauma Cancer dominant trait, and the family history is often positive for a throm- Surgery Diabetes botic tendency. Tissue necrosis Homocystinuria Hyperhomocysteinemia Transfusion necrosis Hyperlipidemia Presence of lupuslike Although hyperhomocysteinemia is more commonly associated Drugs anticoagulant with cardiac disease and arterial thrombosis, it may also be associ- Estrogens Severe infection ated with an increased incidence of venous thromboembolism.124 Drug reactions and interactions Pregnancy This association is not as strong as those already discussed (see Heparin platelet antibody above). Accordingly, anticoagulation of asymptomatic patients Warfarin with elevated homocysteine levels is not currently recommended. Dysfibrinogenemia ity falls below 70% of normal.121 More than 100 qualitative abnormalities of fibrinogen (dysfib- Patients with congenital antithrombin deficiency frequently pre- rinogenemias) have been reported.125 Dysfibrinogenemias are in- sent after a stressful event.They usually have DVT but sometimes herited in an autosomal dominant manner, with most patients be- have PE. If anticoagulation is not contraindicated, the treatment of ing heterozygous. Most patients with dysfibrinogenemia have either choice is heparin at a dosage sufficient to raise the aPTT to the no clinical symptoms or symptoms of a bleeding disorder; a minor- desired level, followed by warfarin. If anticoagulation is con- ity (about 11%) have clinical features of a recurrent thromboem- traindicated (as it is during the peripartum period), antithrombin bolic disorder.126,127 Congenital dysfibrinogenemias associated with concentrate should be given to raise the antithrombin activity to thrombosis account for about 1% of cases of unexplained venous 80% to 120% of normal during the period when anticoagulants thrombosis occurring in young people. The most commonly ob- cannot be given. served functional defect in such dysfibrinogenemias is abnormal Acquired antithrombin deficiency is a well-recognized entity. In fibrin monomer polymerization combined with resistance to fibri- most patients undergoing severe systemic stress, antithrombin lev- nolysis. Decreased binding of plasminogen and increased resis- els fall below normal.122 Patients with classic risk factors for venous tance to lysis by plasmin have been noted. thromboembolism tend to have the lowest levels. In addition to a prolonged TT, patients who have dysfibrino- genemia associated with thromboembolism may have a prolonged Protein C and Protein S Deficiency INR. The diagnosis is confirmed if the reptilase time is also pro- Protein C is a 62 kd glycoprotein with a half-life of 6 hours. longed. Measured with clotting techniques, fibrinogen levels may Because it is vitamin K dependent, a deficiency will develop in the be slightly or moderately low; measured immunologically, levels absence of vitamin K. Acquired protein C deficiency is seen in liver may be normal or even increased. disease, malignancy, infection, the postoperative state, and dissem- Dysfibrinolysis inated intravascular coagulation.49 Protein C deficiency occurs in approximately 4% to 5% of patients younger than 40 to 45 years Fibrinolysis can be impaired by inherited deficiencies of plas- who present with unexplained venous thrombosis.123 It is trans- minogen, defective release of t-PA from the vascular endothelium, mitted as an autosomal dominant trait, and the family history is and high plasma levels of regulatory proteins (e.g., t-PA inhibi- usually positive for a clotting tendency. Protein C levels range from tors).127,128 In addition, factor XII (contact factor) deficiency may 70% to 164% of normal in patients without a clotting tendency; induce failure of fibrinolysis activation. levels below 70% of normal are associated with a thrombotic ten- Inherited plasminogen deficiency is probably only rarely respon- dency. The most appropriate tests for screening are functional sible for unexplained DVT in young patients. It is transmitted as an assays; there are cases of dysfunctional protein C deficiency in autosomal dominant trait. In heterozygous persons with a throm- botic tendency, plasminogen activity is about one half normal (3.9 to 8.4 µmol/ml).The euglobulin clot lysis time is prolonged. Func- tional assays should be carried out, and there should be full trans- Table 7—Congenital Clotting Disorders formation of plasminogen into plasmin activators. The important role of t-PA inhibitors I and II in the regulation Prothrombin G20210A mutation of fibrinolysis is well defined.128,129 In normal plasma, t-PA inhibitor Activated protein C resistance (Leiden V mutation) I is the primary inhibitor for both t-PA and urokinase. Release of t- Antithrombin deficiency PA inhibitor I by platelets results in locally increased concentrations Proteins C and S deficiency where platelets accumulate. The ensuing local inhibition of fibri- Dysfibrinogenemias nolysis may help stabilize the hemostatic plug. t-PA inhibitor II is Dysfibrinolysis present in and secreted by monocytes and macrophages. Hypoplasminogenemia Factor XII deficiency is a rare cause of impaired fibrinolysis. Impaired release of t-PA Initial contact activation of factor XII not only results in activation High levels of t-PA inhibitor of the clotting cascade and of the inflammatory response but also Factor XII deficiency leads to plasmin generation.This intrinsic activation of fibrinolysis requires factor XII, prekallikrein, and high-molecular-weight ki-
  • 18. © 2005 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 6 VASCULAR SYSTEM 6 VENOUS THROMBOEMBOLISM — 18 ninogen. Patients with factor XII deficiencies can be identified by of choice for long-term prophylaxis and should be given at a a prolonged aPTT in the absence of clinical bleeding.107,130 dosage sufficient to maintain an INR of 2.0 to 3.0. When antico- agulation is contraindicated, a purified form of antithrombin may TREATMENT be administered directly. Patients with acquired antithrombin defi- Treatment of a clinical hypercoagulable state involves both pro- ciency should receive prophylaxis in the form of heparin at a phylaxis [see Prophylaxis against Thromboembolism, above] and dosage sufficient to raise the aPTT 5 seconds above the upper limit specific treatment.131 Prophylaxis in postoperative patients consists of the normal laboratory value. primarily of maintaining good hydration, ensuring normal cardiac Treatment of clotting states related to protein C or protein S output, and early mobilization. Low-dose heparin, intermittent deficiency involves administering fresh frozen plasma or factor IX pneumatic compression, low-molecular-weight dextran, or some concentrate. Therapeutic-dose heparin followed by warfarin may combination of these may also be appropriate. be appropriate for long-term treatment. Patients with activated protein C resistance who present with Treatment of thromboembolism associated with dysfibrinogen- venous thrombosis should be treated with heparin in the standard emia involves therapeutic-dose heparin followed by long-term war- fashion. They also should receive genetic counseling and refrain farin.Treatment of thromboembolic disorders associated with dys- from using oral contraceptives. fibrinolysis is essentially the same as that of dysfibrinogenemia. Treatment of antithrombin deficiency associated with active Some patients with these qualitative plasminogen defects and clotting involves initiating heparin anticoagulation at a dosage suf- acute massive thrombotic events may not respond to fibrinolytic ficient to ensure a significant rise in the aPTT.Warfarin is the drug treatment with urokinase or streptokinase. References 1. Dunmire SM: Pulmonary embolism. Emerg Med 16. Christen Y,Wutschert R,Weimer D, et al: Effects of tion of venous thromboembolism after elective Clin North Am 7:339, 1989 intermittent pneumatic compression on venous major knee surgery. Steering Committee of the 2. Shackford SR, Moser KM: Deep venous thrombo- haemodynamics and fibrinolytic activity. Blood Co- Pentasaccharide in Major Knee Surgery Study. N sis and pulmonary embolism in trauma patients. J agul Fibrinol 8:185, 1997 Engl J Med 345:1305, 2001 Intensive Care Med 3:87, 1988 17. Comerota AJ, Chouhan V, Harada RN, et al: The 28. MacCallum PK, Thomson JM, Poller L: Effects of 3. Hirsh J, Hull RD:Venous Thromboembolism: Nat- fibrinolytic effects of intermittent pneumatic com- fixed minidose warfarin on coagulation and fibri- ural History, Diagnosis, and Management. CRC pression: mechanism of enhanced fibrinolysis. Ann nolysis following major gynaecological surgery. Press, Boca Raton, Florida, 1988 Surg 226:306, 1997 Thromb Haemost 64:511, 1990 4. Bergqvist D: Postoperative Thromboembolism: Fre- 18. Elliott CG, Dudney TM, Egger M, et al: Calf-thigh 29. Decousus H, Leizorovicz A, Parent F, et al: A clin- quency, Etiology, Prophylaxis. Springer-Verlag, sequential pneumatic compression compared with ical trial of vena caval filters in the prevention of New York, 1983 plantar venous pneumatic compression to prevent pulmonary embolism in patients with proximal deep-vein thrombosis after non–lower extremity deep-vein thrombosis. N Engl J Med 338:409, 5. Kakkar VV, Stringer MD: Prophylaxis of venous trauma. J Trauma 47:25, 1999 1998 thromboembolism.World J Surg 14:670, 1990 19. Howard A, Zaccagnini D, Ellis M, et al: Random- 30. Belcaro G, Nicolaides AN, Errichi BM, et al: 6. 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